Tag Archives: #huntington

Autophagy May Be The Key To Finding Treatments For Early Huntington’s Disease (Neuroscience)

Autophagy disruption may be at the root of early cognitive changes in Huntington’s disease and is a potential target for disease-modifying therapies, report scientists in the Journal of Huntington’s Disease

Huntington’s Disease (HD) is a progressive neurodegenerative condition characterized by motor, cognitive, and psychiatric symptoms, and motor symptoms are often preceded by cognitive changes. Recent evidence indicates that autophagy plays a central role in synaptic maintenance, and the disruption in autophagy may be at the root of these early cognitive changes. Understanding this mechanism better may help researchers develop treatments for patients with HD early in their disease progression, report scientists in a review article published in the Journal of Huntington’s Disease.

In this review, experts describe how autophagy, the cellular process responsible for clearing old or damaged parts of the cell, plays a critical role supporting synaptic maintenance in the healthy brain, and how autophagy dysfunction in HD may thereby lead to impaired synaptic maintenance and thus early manifestations of disease. The line of research discussed in this review represents a previously unexplored avenue for identifying potential disease-modifying therapies for HD.

“Like many neurodegenerative conditions affecting primarily cognition, such as Alzheimer’s disease, preclinical and clinical data indicate that synapses, the part of brain cells responsible for communication between cells, are affected early in HD,” explained Hilary Grosso Jasutkar, MD, PhD, Department of Neurology, Columbia University, and Ai Yamamoto, PhD, Departments of Neurology and Pathology and Cell Biology, Columbia University, New York, NY, USA. “We have long thought that autophagy played a role in the pathophysiology of HD, but what this role is has been unclear until recently. Recent evidence indicates that autophagy may be important in maintaining the synapse. This line of research has the potential to lead to identification of a drug target to treat HD early in the disease process.”

The authors first explore how cognitive dysfunction is an early manifestation of HD, and that similarly to other neurodegenerative diseases that primarily affect cognition, such as Alzheimer’s disease, dementia with Lewy bodies, and frontotemporal dementia, early deficits in synaptic function may underlie these cognitive symptoms. Next, they review the growing evidence that the lysosome-mediated degradation pathway autophagy plays a central role in synaptic maintenance, and how the disruption in autophagy may contribute to early cognitive changes in HD.

The authors conclude that there are pathologic and imaging data in individuals with mutations in the Huntingtin protein (mHtt), as well as evidence from animal models with HD, that suggest that synapse dysfunction may occur early in HD, prior to cell death.

“Autophagy plays a specialized role in the maintenance and function of the synapse, and mHtt may disrupt this function, leading to the early synaptic changes seen in HD patients and model systems,” explained Dr. Grosso Jasutkar. “These synaptic changes may then manifest as impairments in synaptic plasticity and thus cognitive changes early in the disease course. Given that neurons rely on synaptic input and feedback for cell health, it is possible that this disruption in synaptic signaling in and of itself contributes to cell death in HD.”

“There is much work yet to be done in this field,” added Dr. Yamamoto. “Although various groups have demonstrated individual components of this pathway, a direct causal relationship of mutant Htt leading to synaptic dysfunction and, in turn, cognitive impairments, has yet to be demonstrated.”

“If the model described here is borne out, therapeutics aimed at enhancing the efficiency of synaptic autophagy early in the course of HD could be protective against early cognitive changes and potentially degeneration itself,” concluded the authors.

HD is a fatal genetic neurodegenerative disease that causes the progressive breakdown of nerve cells in the brain. An estimated 250,000 people in the United States are either diagnosed with, or at risk for, the disease. Symptoms include personality changes, mood swings and depression, forgetfulness and impaired judgment, unsteady gait, and involuntary movements (chorea). Every child of an HD parent has a 50% chance of inheriting the gene. Patients typically survive 10-20 years after diagnosis.

Featured image: Proposed pathway of mutant huntingtin (mHtt) contribution to cognitive dysfunction and cell death through impairments in synaptic autophagy: the Huntingtin protein (mHtt) interferes with autophagic efficiency, leading to a decline in synaptic autophagy. This may in turn interfere with synaptic plasticity, causing both cognitive dysfunction and loss of normal synaptic input to post-synaptic cells and feedback to presynaptic cells. Loss of normal synaptic feedback and input may then contribute to cell death. Credit: Journal of Huntington’s Disease.


Reference: Grosso Jasutkar, Hilary and Yamamoto, Ai. ‘Do Changes in Synaptic Autophagy Underlie the Cognitive Impairments in Huntington’s Disease?’ 1 Jan. 2021 : 227 – 238.


Provided by IOS Press

Gene Therapy in Early Stages of Huntington’s Disease May Slow Down Symptom Progression (Neuroscience)

In a new study on mice, Johns Hopkins Medicine researchers report that using MRI scans to measure blood volume in the brain can serve as a noninvasive way to potentially track the progress of gene editing therapies for early-stage Huntington’s disease, a neurodegenerative disorder that attacks brain cells. The researchers say that by identifying and treating the mutation known to cause Huntington’s disease with this type of gene therapy, before a patient starts showing symptoms, it may slow progression of the disease.

The findings of the study were published May 27 in the journal Brain.

“What’s exciting about this study is the opportunity to identify a reliable biomarker that can track the potential success of genetic therapies before patients start manifesting symptoms,” says Wenzhen Duan, M.D., Ph.D., director of the translational neurobiology laboratory and professor of psychiatry and behavioral sciences at the Johns Hopkins University School of Medicine. “Such a biomarker could facilitate the development of new treatments, and help us determine the best time to begin them.”

Huntington’s disease is a rare genetic disorder caused by a single defective gene, dubbed “huntingtin,” on human chromosome 4. The gene is passed on from parents to children — if one parent has the mutation, each child has a 50% chance of inheriting it. Huntington’s disease has no cure and can lead to emotional disturbances, loss of intellectual abilities and uncontrolled movements. Thanks to genetic testing, people can know if they have the disease long before symptoms arise, which typically happens in their 40s or 50s.

For the study, Duan and her team collaborated with colleagues from Kennedy Krieger Institute in Baltimore, Maryland, who developed a novel method to more precisely measure the blood volume in the brain by using advanced functional MRI scans. With the scans, they can map the trajectory of blood flow in small blood vessels called arterioles in the brains of mice engineered to carry the human huntingtin gene mutation that mirror the early stages of Huntington’s disease in humans.

Duan notes that there are many known metabolic changes in the brains of people with Huntington’s disease, and those changes initiate a brain blood volume response in the disease’s early stages. Blood volume is a key marker for oxygen supply to brain cells, which in turn supplies energy for the neurons to function. But with Huntington’s disease, the brain’s arteriolar blood volume is dramatically diminished, which makes the neurons deteriorate because of lack of oxygen as the disease progresses.

In a series of experiments, the researchers suppressed the mutation in the huntingtin gene in mice, using a gene-editing technology known as CRISPR — a tool for editing genomes that allows the alteration of a DNA sequence to modify gene function. Then, they used the MRI scanning technique and other tests to track the brain function over time both of mice with the huntingtin mutation, in which they edited out the faulty gene sequence, and a control group of mice in which the faulty gene was unedited.

The experiments assessed abnormalities in the trajectory of arteriolar blood volumes in mouse brains with the Huntington’s disease mutation at 3, 6 and 9 months of age (pre-symptom stage, beginning of symptoms and post-symptom stage, respectively). The researchers looked at whether suppression of the mutant huntingtin gene in the neurons could normalize altered arteriolar blood volumes in the pre-symptom stage, and whether reduced expression of the huntingtin gene at the pre-symptom stage could delay or even prevent development of symptoms.

“Overall, our data suggest that the cerebral arteriolar blood volume measure may be a promising noninvasive biomarker for testing new therapies in patients with Huntington’s who are yet to show symptoms of the disease,” says Duan. “Introducing treatment in this early stage may have long-lasting benefits.”

When the researchers mapped the trajectory of cerebral blood volume and conducted an assortment of brain and motor tests in the mice at 3 months of age, and compared the test to those of the control group, they observed no significant differences except in cerebral blood volumes. However, Huntington’s symptoms in the mice with the huntingtin gene started at 6 months of age and progressively worsened at 9 months, suggesting that altered cerebral blood volume occurs before motor symptoms and atrophy of the brain cells — typical traits of the disease.

The cerebral blood volume changes were also found to be similar to those observed in patients with Huntington’s disease before they start manifesting symptoms, which declines with the start of symptoms and while the disease progresses over time.

The researchers also analyzed the structure of the arteriole blood vessels in the brains of mice with the mutant huntingtin gene at 3 and at 9 months of age and found no differences in the numbers of vessel segments in the pre-symptom stage. However, they observed that smaller blood vessels had an increased density and reduced diameter, which may be a vascular response to compensate for the impaired neuronal brain function. This might suggest, the researchers conclude, that impaired vascular structure leads to lowered arteriole blood volumes and possibly compromised ability to compensate for the loss in the symptom stage.

Considering that Huntington’s disease symptoms depend not only on brain cell loss but also on how neurons deteriorate, the researchers set out to determine if suppressing the huntingtin gene during the pre-symptom stage in mice could delay or even prevent disease progression. To do that, the researchers introduced the altered huntingtin gene to the neurons in mice at 2 months of age and evaluated the outcomes at 3 months of age (when no atrophy or motor deficits were present).

Remarkably, the researchers say, the cerebral arteriolar blood volume in mice with the altered huntingtin gene was This suggests that the altered cerebral blood volume during the pre-symptom stage in mice is most likely due to neuronal changes in either activity or metabolism.

“Our findings demonstrate that significant changes in arteriolar cerebral blood volumes occur before neurons start to degenerate and symptoms begin, further supporting the idea that altered cerebrovascular function is an early stage symptom in Huntington’s disease,” says Duan. She explains that these changes also indicate there’s a pre-symptom therapeutic window in which to test interventions. While no animal model replicates all the symptoms of human Huntington’s disease, this research offers an alternative system to study functional changes in the pre-symptom stage, she says.

Further validation of these findings in human clinical trials would facilitate development of efficient therapeutic interventions for patients with Huntington’s disease before they start developing symptoms. “The goal is to delay or even conceivably prevent the manifestation of Huntington’s disease altogether,” says Duan.

Along with Duan, other researchers who contributed to the work are Hongshuai Liu, Chuangchuang Zhang, Jing Jin, Liam Cheng, Qian Wu, Zhiliang Wei, Peiying Liu and Christopher Ross from Johns Hopkins, and Jiadi Xu, Xinyuan Miao, Hanzhang Lu, Peter van Zijl and Jun Hua from the Kennedy Krieger Institute and Johns Hopkins.

Featured image: Representative cerebral blood volume maps in mouse brains from indicated genotypes and treatment groups. Top row shows the raw images — the red regions of interest indicate the quantified brain region. Bottom row shows the representative cerebral blood volume maps in the mice at the indicated genotypes and treatment at 3 months of age. The scale bars are shown on the right. Warmer color represents higher cerebral blood volume values. © Wenzhen Duan, M.D., Ph.D.


Reference: Hongshuai Liu, Chuangchuang Zhang, Jiadi Xu, Jing Jin, Liam Cheng, Xinyuan Miao, Qian Wu, Zhiliang Wei, Peiying Liu, Hanzhang Lu, Peter C M van Zijl, Christopher A Ross, Jun Hua, Wenzhen Duan, Huntingtin silencing delays onset and slows progression of Huntington’s disease: a biomarker study, Brain, 2021;, awab190, https://doi.org/10.1093/brain/awab190


Provided by Johns Hopkins Medicine

Glial Cells Help Mitigate Neurological Damage in Huntington’s Disease (Neuroscience)

The brain is not a passive recipient of injury or disease. Research has shown that when neurons die and disrupt the natural flow of information they maintain with other neurons, the brain compensates by redirecting communications through other neuronal networks. This adjustment or rewiring continues until the damage goes beyond compensation.

This process of adjustment, a result of the brain’s plasticity, or its ability to change or reorganize neural networks, occurs in neurodegenerative conditions such as Alzheimer’s, Parkinson’s and Huntington’s disease (HD). As the conditions progress, many genes change the way they are normally expressed, turning some genes up and others down. The challenge for researchers like Dr. Juan Botas who studies HD, has been to determine which of the gene expression changes are involved in causing the disease and which ones help mitigate the damage, as this may be critical for designing effective therapeutic interventions.

Dr. Juan Botas © BCM

In his lab at Baylor College of Medicine, Botas and his colleagues look to understand what causes the loss of communication or synapses between neurons in HD. Up until now, research has focused on neurons because the normal huntingtin gene, whose mutation causes the condition, contributes to maintaining healthy neuronal communication. In the current work, the researchers looked into synapses loss in HD from a different perspective.

Focusing on glia to understand Huntington’s disease

The mutated huntingtin gene is not only present in neurons, but in all the cells in the body, opening the possibility that other cell types also could be involved in the condition.

“In this study we focused on glia cells, which are a type of brain cell that is just as important as neurons to neuronal communication,” said Botas, professor of molecular and human genetics and of molecular and cellular biology at Baylor and a member of the Jan and Dan Duncan Neurological Research Institute at Texas Children’s Hospital.

We thought that glia might be playing a role in either contributing or compensating for the damage observed in Huntington’s disease.”

Initially thought to be little more than housekeeping cells, glia turned out to have more direct roles in promoting normal neuronal and synaptic function.

In a previous work, Botas and his colleagues studied a fruit fly model of HD that expresses the human mutant huntingtin (mHTT) gene in neurons, to understand which of the many gene expression changes that occur in HD are causing disease and which ones are compensatory.

“One class of compensatory changes affected genes involved in synaptic function. Could glia be involved?” Botas said. “To answer this question, we created fruit flies that express mHTT only in glia, only in neurons or in both cell types.”

Comparing changes in gene expression

The researchers began their investigation by comparing the changes in gene expression present in the brains of healthy humans with those in human HD subjects and in HD mouse and fruit fly models. They identified many genes whose expression changed in the same direction across all three species but were particularly intrigued when they discovered that having HD reduces the expression of glial cell genes that contribute to maintaining neuronal connections.

“To investigate whether the reduction of expression of these genes in glia either helped with disease progression or with mitigation, we manipulated each gene either in neurons, glial cells or both cell types in the HD fruit fly model. Then we determined the effect of the gene expression change on the function of the flies’ nervous system,” Botas said.

They evaluated the flies’ nervous system health with a high-throughput automated system that assessed locomotor behavior quantitatively. The system filmed the flies as they naturally climbed up a tube. Healthy flies readily climb, but when their ability to move is compromised, the flies have a hard time climbing. The researchers looked at how the flies move because one of the characteristics of HD is progressive disruption of normal body movements.

Turning down the genes worked

The results revealed that in HD, turning down glial genes involved in synaptic assembly and maintenance is protective.

Fruit flies with the mutant huntingtin gene in their glial cells in which the researchers had deliberately turned down synaptic genes climbed up the tube better than flies in which the synaptic genes were not dialed down.

“Our study reveals that glia affected by HD respond by tuning down synapse genes, which has a protective effect,” Botas said. “Some gene expression changes in HD promote disease progression, but other changes in gene expression are protective. Our findings suggest that antagonizing all disease-associated alterations, for example using drugs to modify gene expression profiles, may oppose the brain’s efforts to protect itself from this devastating disease. We propose that researchers studying neurological disorders could deepen their analyses by including glia in their investigations.”

For a complete list of contributors, their affiliations and financial support for this work, go to the publication in eLife.

Featured image: Confocal microscopy image showing the striatum in a mouse model of Huntington’s Disease. The astrocytes are visualized in green and cell nuclei in blue. Image courtesy of J. Botas/eLife, 2021.


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New Study Finds Abnormal Response to Cellular Stress is Associated With Huntington’s Disease (Neuroscience)

A new University of California, Irvine-led study finds that the persistence of a marker of chronic cellular stress, previously associated with neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), also takes place in the brains of Huntington’s disease (HD) patients.

Chronic cellular stress results in the abnormal accumulation of stress granules (SGs), which are clumps of protein and RNAs that gather in the cell. Prior to this study, published in the Journal of Clinical Investigation, it was not known if these types of granules were a pathological feature of HD, an inherited and progressive neurodegenerative disorder that typically strikes in the prime of life.

In addition to identifying SGs as a pathological feature of HD, researchers made several other discoveries including that extracellular vesicles, which float in cerebrospinal fluid (CSF) and act as a messaging system between cells in the brain, can potentially alter the behavior of other cells and impact the abnormal accumulation of the granules. They also found that TAR DNA-binding protein 43 (TDP43) is mislocalized, which has emerged as a critical feature of multiple neurodegenerative diseases.

“We were initially interested in whether the profile of these messages could serve as a biomarker for HD and investigated whether the vesicles from HD patients contain messages that are different from those of unaffected individuals,” said first author Isabella I. Sanchez, PhD, from the Thompson Laboratory at UCI School of Medicine.

Researchers found that the CSF of HD patients carried messages in the form of small non-coding RNAs (miRNAs) that did were predicted to alter the production of proteins that are indispensable for SG formation. They soon identified a key player in SG dynamics, GTPase-activating protein-binding protein 1 (G3BP1), as a predicted target.

“This finding regarding the miRNAs was very exciting, as we had simultaneously started investigations to characterize SGs in HD brain tissues.  SGs can be very difficult to detect in brain tissues, and it just so happened that we had narrowed down the adequate conditions and were ready to being characterizing G3BP1 SGs in HD mouse and HD patient brains,” said Leslie M. Thompson, PhD, Donald Bren and UCI Chancellor’s professor in the Departments of Psychiatry & Human Behavior and Biological Chemistry at the UCI School of Medicine, and Neurobiology and Behavior at the UCI School of Biological Sciences.   

While SG formation is a normal physiological process that enables cells to overcome stressful conditions, the SG pathology in HD may result from an accumulation G3BP1 SGs that initially served a protective function, but develop into hyper-stable structures over time.

“We hope that our findings will inform future studies aimed at understanding how SG accumulation affects HD progression, and whether targeting SG pathology is a viable therapeutic avenue in the fight against HD,” said Robert Spitale, PhD, professor in the Department of Pharmaceutical Sciences and also a lead author of the study.

This research was supported in part by grants from the Medical Research Council, CHDI Foundation, the National Institutes of Health, Chan Zuckerberg Initiative, National Center for Research Resources, National Center for Advancing Translational Sciences, and the UCI Institute for Clinical & Translational Science.

Featured image: Shown is a surface rendering of G3BP1 granules (in green) detected by immunofluorescence in the HD mouse model cortex. © UCI School of Medicine


Reference: Isabella I. Sanchez, … , Robert C. Spitale, Leslie M. Thompson, “Huntington’s disease mice and human brain tissue exhibit increased G3BP1 granules and TDP43 mislocalization”, J Clin Invest. 2021;131(12):e140723. https://doi.org/10.1172/JCI140723.


Provided by UCI School of Medicine

Huntington’s Disease Driven By Slowed Protein-building Machinery in Cells (Neuroscience)

New study shows that mutant huntingtin protein slows ribosomes

In 1993, scientists discovered that a single mutated gene, HTT, caused Huntington’s disease, raising high hopes for a quick cure. Yet today, there’s still no approved treatment.

One difficulty has been a limited understanding of how the mutant huntingtin protein sets off brain cell death, says neuroscientist Srinivasa Subramaniam, PhD, of Scripps Research, Florida. In a new study published in Nature Communications on Friday, Subramaniam’s group has shown that the mutated huntingtin protein slows brain cells’ protein-building machines, called ribosomes.

“The ribosome has to keep moving along to build the proteins, but in Huntington’s disease, the ribosome is slowed,” Subramaniam says. “The difference may be two, three, four-fold slower. That makes all the difference.”

Cells contain millions of ribosomes each, all whirring along and using genetic information to assemble amino acids and make proteins. Impairment of their activity is ultimately devastating for the cell, Subramaniam says.

“It’s not possible for the cell to stay alive without protein production,” he says.

The team’s discoveries were made possible by recent advancements in gene translation tracking technologies, Subramaniam says. The results suggest a new route for development of therapeutics, and have implications for multiple neurodegenerative diseases in which ribosome stalling appears to play a role.

Huntington’s disease affects about 10 people per 100,000 in the United States. It is caused by an excessive number of genetic repeats of three DNA building blocks. Known by the letters CAG, short for cytosine, adenine and guanine, 40 or more of these repeats in the HTT gene causes the brain degenerative disease, which is ultimately fatal. The more repeats present, the earlier the onset of symptoms, which include behavioral disturbances, movement and balance difficulty, weakness and difficulty speaking and eating. The symptoms are caused by degeneration of brain tissue that begins in a region called the striatum, and then spreads. The striatum is the region deep in the center of the brain that controls voluntary movement and responds to social reward.

For their experiments, the scientists used striatal cells engineered to have three different degrees of CAG repeats in the HTT gene. They assessed the impact of the CAG repeats using a technology called Ribo-Seq, short for high-resolution global ribosome footprint profiling, plus mRNA-seq, a method that allows a snapshot of which genes are active, and which are not in a given cell at a given moment.

The scientists found that in the Huntington’s cells, translation of many, not all, proteins were slowed. To verify the finding, they blocked the cells’ ability to make mutant huntingtin protein, and found the speed of ribosome movement and protein synthesis increased. They also assessed how mutant huntingtin protein impacted translation of other genes, and ruled out the possibility that another ribosome-binding protein, Fmrp, might be causing the slowing effect.

Further experiments offered some clues as to how the mutant huntingtin protein interfered with the ribosomes’ work. They found it bound directly to ribosomal proteins and the ribosomal assembly, and not only affected speed of protein synthesis, but also of ribosomal density within the cell.

Many questions remain, Subramaniam says, but the advance offers a new direction for helping people with Huntington’s disease.

“The idea that the ribosome can stall before a CAG repeat is something people have predicted. We can show that it’s there,” Subramaniam says. “There’s a lot of additional work that needs to be done to figure out how the CAG repeat stalls the ribosome, and then perhaps we can make medications to counteract it.”

In addition to Subramaniam, the authors of the paper, “Mutant Huntingtin Stalls Ribosomes and Represses Protein Synthesis in a Cellular Model of Huntington Disease,” include Mehdi Eshraghi, Pabalu Karunadharma, Neelam Shahani, Nicole Galli, Manish Sharma, Uri Nimrod Ramírez-Jarquín, Katie Florescu, and Jennifer Hernandez of Scripps Research; Juliana Blin and Emiliano P Ricci of the RNA Metabolism in Immunity and Infection Lab, Laboratory of Biology and Cellular Modelling of Lyon, France; Audrey Michel of RiboMaps of Cork, Ireland; and Nicolai Urban of the Max Planck Neuroscience Institute in Jupiter, Florida.

Featured image: Disease-causing huntingtin, shown in red, interacts with ribosomes, shown in green, in a striatal neuron. The nucleus is blue. © Image by Nicolai Urban of Max Planck Institute for Neuroscience in Jupiter, Florida.


Reference: Eshraghi, M., Karunadharma, P.P., Blin, J. et al. Mutant Huntingtin stalls ribosomes and represses protein synthesis in a cellular model of Huntington disease. Nat Commun 12, 1461 (2021). https://www.nature.com/articles/s41467-021-21637-y https://doi.org/10.1038/s41467-021-21637-y


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New Therapeutic Target for Huntington’s Treatment (Medicine)

New perspective on the role of sRNAs in the disease

Huntington’s disease is caused by a mutation in the Huntingtin gene (HTT), which appears in adults and features motor, cognitive and psychiatric alterations. The origin of this disease has been associated with the anomalous functioning of the mutated protein: mHTT, but recent data showed the involvement of other molecular mechanisms.

A new study conducted by the University of Barcelona has identified a type of ribonucleic acid (RNA) as a potential therapeutic target for the treatment of the disease. These are the small RNA, or sRNAs, molecules that do not code proteins but have important functions in the regulation of gene expression. According to the study, sRNAs would take part in the development of the disease, results that shed light on the design of new specific drugs to block the activity of these intermediary molecules that help researchers to understand the information in the genes.

From left to right: Mercè Masana, Ana Gámez-Valero, Eulàlia Martí, Anna Guisado-Corcoll, Esther Pérez-Navarro and Maria Solaguren-Beascoa. © UNIVERSITY OF BARCELONA

The study, published in the journal Acta Neuropathologica, counts on the participation of two teams from the Institute of Neurosciences of the UB, led by the lecturers of the Faculty of Medicine and Health Sciences Eulàlia Martí, also researcher at the Epidemiology and Public Health Networking Biomedical Research Centre (CIBERESP); and Esther Pérez-Navarro, also researcher at the Biomedical Research Networking Center on Neurodegenerative Diseases (CIBERNED) and the August Pi i Sunyer Biomedical Research Institute (IDIBELL), the Center for Genomic Regulation (CRG) and the University Medical Center Göttingen (Germany).

An innovative technique

The objective of the researchers in the study was to understand the toxic potential of the series of sRNAs that are created in the brain of patients with Huntington’s disease. The researchers note that the identification of toxicity mechanisms is important to understand how the disease evolves and to design the right drugs and therapeutic strategies.

In order to solve this question, researchers isolated sRNAs from the brain of patients with Huntington’s and from people without this disease, to use them as a comparative model. Then, they administrated these molecules in the brain of normal mice and analyse whether the mice developed anomalies similar to those in the human disease. “This is the first time we use a human-origin RNA injection in mice’s brain and this innovative strategy enabled us to understand the importance of these molecules independently from the protein”, notes Eulàlia Martí.

The results of this experiment show that sRNAs in patients with Huntington’s are enough to cause a similar pathology in normal mice, which includes “motor alterations, transcriptional changes similar to those observed in the human disease and mice models, specific affectation of the most affected neuronal type during the course of the disease, neuronal loss and neuroinflammation”, says the researcher.

New perspective on the role of sRNAs in the disease

These results suggest a new view on the role of the different types of sRNAs in the progression of the disease. “To date, researchers showed that both the mHTT protein and the RNA that codes it and which has CAG repeats, contribute to neurotoxicity. However, toxic effects related to RNAs with CAG repeats do not explain certain alterations that are important within the context of the pathology, for instance, the specific neuronal affectation or transcriptional alterations. These results -the researcher continues-, show different types of sRNAs created in the patients’ brains would be likely to take part in the pathogenesis”.

In this sense, the study shows that derived fragments of RNAs, tRNA fragments (tRFs), are the most altered type of sRNAs in the brain of patients with Huntington’s. The study shows that a specific tRF can cause neurotoxicity, suggesting that tRFS could participate in the damaging effects related to sRNAs in the affected patients. After this study, the main objective is to understand the functional relevance of different classes of sRNAs, with special emphasis on tRFs that are abundant in affected human brains. “Understanding the dynamics of the expression of toxic classes in brain regions and in the evolution of the disease is crucial to have a full view of their implication in the pathological process”, highlights Eulàlia Martí.

Potential biomarkers

Moreover, these molecules could become potential biomarkers of the disease, since there is multiple evidence to show that changes in the RNAs expression occur before the manifestation of the symptoms. Authors say that “these changes can be reflected in biofluids such as plasma and this fact can grant these types a great value as biomarkers”.

Last, these results could have implications in the treatment of other diseases. “Alterations in the sRNAs expression are detected early in many neurodegenerative diseases, and therefore, we can find a broader study field to understand what classes can contribute to specific aspects related to neurodegeneration and neuroinflammation”, the researcher concludes.

Featured image: Jordi Creus Muncunill © UNIVERSITY OF BARCELONA


Reference: Creus-Muncunill J, Guisado-Corcoll A, Venturi V, Pantano L, Escaramís G, García de Herreros M, Solaguren-Beascoa M, Gámez-Valero A, Navarrete C, Masana M, Llorens F, Diaz-Lucena D, Pérez-Navarro E, Martí E. Huntington’s disease brain-derived small RNAs recapitulate associated neuropathology in mice. Acta Neuropathol. 2021 Feb 6. doi: 10.1007/s00401-021-02272-9. Epub ahead of print. PMID: 33547932.


Provided by University of Barcelona

Basic Cell Health Systems Wear Down in Huntington’s Disease, Novel Analysis Shows (Medicine)

Using an innovative computational approach to analyze vast brain cell gene expression datasets, researchers at MIT and Sorbonne Université have found that Huntington’s disease may progress to advanced stages more because of a degradation of the cells’ health maintenance systems than because of increased damage from the disease pathology itself.

The analysis yielded a trove of specific gene networks governing molecular pathways that disease researchers may now be able to target to better sustain brain cell health amid the devastating neurodegenerative disorder, said co-senior author Myriam Heiman, Associate Professor in MIT’s Department of Brain and Cognitive Sciences and an investigator at The Picower Institute for Learning and Memory. Christian Neri of the Sorbonne’s Centre National de la Recherche Scientifique is the co-senior and co-corresponding author of the study published in eLife.

“If we can maintain the expression of these compensatory mechanisms, it may be a more effective therapeutic strategy than just trying to affect one gene at a time,” said Heiman, who is also a member of the Broad Institute of MIT and Harvard.

In the study, the team led by co-corresponding author Lucile Megret created a process called “Geomic” to integrate two large sets of data from Heiman’s lab and one more from UCLA researcher William Yang. Each dataset highlighted different aspects of the disease, such as its effect on gene expression over time, how those effects varied by cell type, and the fate of those cells as gene expression varied.

Geomic created plots of the data that mapped differences pertaining to 4,300 genes along dimensions such as mouse age, the extent of Huntington’s-causing mutation, and cell type (certain neurons and astrocytes in a region of the brain called the striatum are especially vulnerable in Huntington’s). The plots took the form of geometric shapes, like crumpled pieces of paper, whose deformations could be computationally compared to identify genes whose expression changed most consequentially amid the disease. The researchers could then look into how abnormal expression of those genes could affect cellular health and function.

Big breakdowns

The Geomic analysis highlighted a clear pattern. Over time, the cells’ responses to the disease pathology–linked to toxic expansions in a protein called Huntingtin–largely continued intact, but certain highly vulnerable cells lost their ability to sustain gene expression needed for some basic systems that sustain cell health and function. These systems initially leapt into action to compensate for the disease but eventually lost steam.

One of the biggest such breakdowns in an especially vulnerable cell type, Drd-1 expressing neurons, was maintaining the health of energy-producing components called mitochondria. Last year, Heiman’s lab published a study in Neuron showing that in some Huntington’s-afflicted neurons, RNA leaks out of mitochondria provoking a misguided and immune response that leads to cell death. The new findings affirm a key role for mitochondrial integrity and implicate key genes such as Ndufb10 whose diminished expression may be undermine the cell’s network of genes supporting the system.

The Geomic approach also highlighted an especially dramatic decline in the Drd-1 neurons and in astrocytes of expression of multiple genes in pathways that govern endosome regulation, an essential process for determining where proteins go and when they are degraded within the cells. Here, too, key genes like Rab8b and Rab7 emerged as culprits within broader gene networks.

The researchers went on to validate some of their top findings by confirming that key alterations of gene expression were also present in post-mortem samples of brain tissue from human Huntington’s patients.

While mitochondrial integrity and endosome regulation are two particularly strong examples, Heiman said, the study lists many others. The Geomic source code and all the data and visualizations it yielded are publicly accessible on a website produced by the authors.

“We’ve created a database of future targets to probe,” Heiman said.

Neri added: “This database sets a precise basis for studying how to properly re-instate brain cell compensation in Huntington’s disease, and possibly in other neurodegenerative diseases that share common compensatory mechanisms with Huntington’s disease.”

Key among these could be regulators of genetic transcription in these affected pathways, Heiman said.

“One promising future direction is that among the genes that we implicate in these network effects, some of these are transcription factors,” she said. “They may be key targets to bring back the compensatory responses that decline.”

A new way to study disease

While the researchers first applied Geomic’s method of “shape deformation analysis” to Huntington’s disease, it will likely be of equal utility for studying any neurodegenerative disease like Alzheimer’s or Parkinson’s, or even other brain diseases, the authors said.

“This is a new approach to study systems level changes, rather than just focusing on a particular pathway or a particular gene,” said Heiman. “I think this is a really nice proof of principle and hopefully we can apply this type of methodology to the study of other genomic data from other disease studies.”

In addition to Heiman, Neri and Megret, the paper’s other authors are Barbara Gris, Satish Nair, Jasmin Cevost, Mary Wertz, Jeff Aaronson, Jim Rosinski, Thomas Vogt, and Hilary Wilkinson.

The Sorbonne Université, the CHDI Foundation and the National Institutes of Health supported the Research. Heiman’s lab is also supported by the JPB Foundation.

Featured image: Geomic created plots of the data that mapped differences pertaining to 4,300 genes along dimensions such as mouse age, the extent of Huntington’s-causing mutation, and cell type (certain neurons and astrocytes in a region of the brain called the striatum are especially vulnerable in Huntington’s). The plots took the form of geometric shapes, like crumpled pieces of paper, whose deformations could be computationally compared to identify genes whose expression changed most consequentially amid the disease. The researchers could then look into how abnormal expression of those genes could affect cellular health and function. © Sorbonne Université


Reference: Lucile Megret et al., “Shape deformation analysis reveals the temporal dynamics of cell-type-specific homeostatic and pathogenic responses to mutant Huntingtin”, ELife, 2021. https://elifesciences.org/articles/64984


Provided by Picower Institute of technology

New Evidence: Effects of Huntington’s Disease Mutation May begin in Childhood (Medicine)

The neurodevelopmental hypothesis of Huntington’s disease (HD) suggests its origins are rooted in childhood when the mutant gene that causes HD begins to affect both brain and body growth and development, reports the Journal of Huntington’s Disease.

There is growing evidence to support the hypothesis that there is a neurodevelopmental component to the late-onset neurodegeneration occurring in the brain of huntingtin gene (HTT gene) mutation carriers, and that this increased susceptibility to brain cell death begins during childhood. Experts discuss the evidence that the HTT gene mutation affects brain and body growth based on a unique study of children at risk for HD, the Kids-HD study, in a review paper and accompanying research article published in the Journal of Huntington’s Disease.

Theories of the etiology of Huntington’s disease. © Journal of Huntington’s Disease.

The classic concept is that Huntington’s disease is caused by toxic mutant huntingtin (mHTT) acting over time on mature brain cells. However, there is growing evidence for an alternative theory in which mHTT has an effect on brain development and that this altered development plays a vital role in the later degenerative process. This theory is based on the notion that wild-type huntingtin (HTT) function plays a role in normal brain development.

“Although the gene was discovered in 1993, we still don’t have a good understanding of what causes HD – how does the mutant gene cause brain cells to become ‘sick’ then die?” noted lead investigator Peg C. Nopoulos, MD, Department of Psychiatry, Department of Pediatrics, and Department of Neurology, University of Iowa Carver College of Medicine, Iowa City, IA, USA. “The neurodevelopmental hypothesis is a relatively new way of thinking about the disease and can help focus research efforts in a new direction. This review and the accompanying study are important in reshaping our ideas about how we view the nature and timing of preventive treatment for HD and the factors that contribute to disease.”

The neurodevelopmental hypothesis of HD posits that the disease-causing gene mutation affects development of a specific region or specific brain circuit. These cells are abnormal in their growth; however, they are compensated for early in life. Therefore, despite abnormal development, there are no overt symptoms. The abnormally developed cells remain in a “mutant steady state.” These cells are then vulnerable to dysfunction and degeneration later in life when they are subjected to stresses and strains, either normal (programmed synaptic elimination during puberty or through the aging process) or pathological (toxic effects of mHTT). In the end, the disease pathology results in neural degeneration with its accompanying cognitive and motor deficits.

The two papers focus on the most recent findings from Kids-HD, a unique brain imaging study of children aged six to 18 years old at risk for HD because they have a parent or grandparent with HD. The review discusses the effects of mHTT on brain development and the study evaluates the effect of mHTT on body development.

According to the authors, there is evidence in children as young as 6 who carry a mutation in the HTT gene, that production of mHTT alters the growth and development of the striatum and related circuitry. The gene contains a sequence of three DNA bases – cytosine-adenine-guanine (CAG) – repeated multiple times. The developmental changes appear to be influenced by the CAG repeat length and occur well before onset of symptoms of the disease. Deficits may then be compensated for by increased activity in other brain circuits, particularly those involving the cerebellum, and are manifest only when compensatory systems are no longer working.

The body development analysis used data from the 186 children in the Kids-HD study. Investigators applied simple measures of growth – height, weight, and the combined BMI measure – to compare changes in two groups – those who carried the CAG repeat expansion mutation in the HTT gene and those who did not.

Around puberty the study began to show an altered trajectory of growth in HTT gene mutation carriers. The pace at which their BMI increased slowed over time so that at by about 17 years old, that group had substantially lower BMI than the group without the gene mutation. Boys with the gene mutation tended to be taller than the control group, but with lower weight; girls with the gene mutation tended to be around the same height, but lower in weight.

Importantly, although the gene mutation carriers were roughly 30 years from the expected time of onset of the disease, the mutant HTT gene had already affected their growth and development. This work is important because it suggests that the mutation is altering the body even before the onset of neurological disease in midlife.

Gene therapy trials are currently underway to evaluate the effectiveness of drugs to slow disease progression in affected individuals, and future trials will ultimately aim to prevent disease onset by delivery of gene therapy to gene mutation carriers – those with mHTT, but no symptoms.

“Gene therapy trials are finally here. However, interfering with a gene responsible for brain development early in life must be done with an abundance of caution,” commented Dr. Nopoulos. “Understanding how mHTT affects brain development is vital in the context of planning disease prevention therapies.”

HD is a fatal genetic neurodegenerative disease that causes the progressive breakdown of nerve cells in the brain. An estimated 250,000 people in the United States are either diagnosed with, or at risk for, the disease. Symptoms include personality changes, mood swings and depression, forgetfulness and impaired judgment, unsteady gait, and involuntary movements (chorea). Every child of an HD parent has a 50% chance of inheriting the gene. Patients usually survive 10 – 20 years after diagnosis.

Reference: Tereshchenko, Alexander et al. ‘Developmental Trajectory of Height, Weight, and BMI in Children and Adolescents at Risk for Huntington’s Disease: Effect of mHTT on Growth’. 1 Jan. 2020 : 245 – 251. https://content.iospress.com/articles/journal-of-huntingtons-disease/jhd200407

Provided by IOS Press

Researchers Link Cases of ALS and FTD to a Huntington’s Disease-associated Mutation

A study led by researchers at the National Institutes of Health has made a surprising connection between frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS), two disorders of the nervous system, and the genetic mutation normally understood to cause Huntington’s disease.

This large, international project, which included a collaboration between the National Institute of Neurological Disorders and Stroke (NINDS) and the National Institute on Aging (NIA), opens a potentially new avenue for diagnosing and treating some individuals with FTD or ALS.

Several neurological disorders have been linked to “repeat expansions,” a type of mutation that results in abnormal repetition of certain DNA building blocks. For example, Huntington’s disease occurs when a sequence of three DNA building blocks that make up the gene for a protein called huntingtin repeats many more times than normal. These repeats can be used to predict whether someone will develop the illness and even when their symptoms are likely to appear, because the more repeats in the gene, the earlier the onset of disease.

“It has been recognized for some time that repeat expansion mutations can give rise to neurological disorders,” said Sonja Scholz, M.D., Ph.D., investigator, NINDS Intramural Research Program. “But screening for these mutations throughout the entire genome has traditionally been cost-prohibitive and technically challenging.”

Taking advantage of technology available at NIH, the researchers screened the entire genomes from large cohorts of FTD/ALS patients and compared them to those of age-matched healthy individuals. While several patients had a well-established genetic marker for FTD/ALS, a small subset surprisingly had the same huntingtin mutation normally associated with Huntington’s disease. Remarkably, these individuals did not show the classical symptoms of Huntington’s but rather those of ALS or FTD.

“None of these patients’ symptoms would have clued their physicians into thinking that the underlying genetic cause was related to the repeat expansion we see in Huntington’s disease,” said Dr. Scholz.

She continued by explaining that whole genome sequencing is changing how neurological patients can be diagnosed. Traditionally, this has been based on which disease best fit the overall symptoms with treatment aimed at managing those symptoms as best as possible. Now, clinicians can generate genetically defined diagnoses for individual patients, and these do not always align with established symptom-based neurological conditions.

“Our patients simply don’t match a textbook definition of disease when it comes to which mutation produces which symptoms. Here we have patients carrying a pathogenic huntingtin mutation but who present with FTD or ALS symptoms,” said Dr. Scholz.

One implication of these findings is that, if successful, these therapies could be applied to the small subset of FTD and ALS patients with that mutation as well. The researchers note that, while the number of FTD/ALS patients seen with the Huntington’s-linked mutation is small (roughly 0.12-0.14%), adding genetic screening for the mutation to the standard diagnostic procedure for patients showing symptoms of FTD or ALS should be considered.

“Because gene therapy targeting this mutation is already in advanced clinical trials, our work offers real hope to the small number of FTD and ALS patients who carry this mutation,” said Bryan Traynor, M.D., Ph.D., senior investigator, NIA Intramural Research Program. “This type of large-scale international effort showcases the power of genomics in identifying the molecular causes of neurodegenerative diseases and paves the way for personalized medicine.”

Reference: Ramita Dewan et al, Pathogenic Huntingtin Repeat Expansions in Patients with Frontotemporal Dementia and Amyotrophic Lateral Sclerosis, Neuron (2020). DOI: 10.1016/j.neuron.2020.11.005

Provided by National Institutes of Health