Tag Archives: #parkinson

Innovative Gel Offers New Hope to Defeat Parkinson’s Disease (Neuroscience)

Researchers from The Australian National University (ANU), in collaboration with The Florey Institute of Neuroscience and Mental Health, have developed a new type of hydrogel that could radically transform how we treat Parkinson’s disease.
The gel also offers hope for patients who have suffered from other neurological conditions such as strokes.

The new material is made from natural amino acids – the building blocks of proteins – and acts as a gateway to facilitate the safe transfer of stem cells into the brain and restore damaged tissue by releasing a growth-enabling protein called GDNF.

By putting the stem cells into a gel, they are exposed to less stress when injected into the brain and are more gently and successfully integrated. 

“When we shake or apply energy to the hydrogel, the substance turns into a liquid which allows us to inject it into the brain through a very small capillary using a needle,” Professor David Nisbet, from the ANU John Curtin School of Medical Research (JCSMR), said.
“Once inside the brain, the gel returns to its solid form and provides support for the stem cells to replace lost dopamine neurons.”
Professor Clare Parish, Head of the Stem Cell and Neural Development Laboratory at The Florey Institute, said: “Through use of the hydrogel technique we demonstrated increased survival of the grafted dopamine neurons and restored movement in an animal model of Parkinson’s disease.”
Although dopamine-related drugs are a readily used treatment for people living with Parkinson’s disease, many have undesirable side effects that are exacerbated with time.
“The stem cell transplant delivered in this hydrogel on the other hand avoids many of these side effects and could provide a one-off intervention that can sustain dopamine levels for decades to come,” Professor Parish said.
Professor Nisbet said the hydrogel has the potential to also treat patients who have suffered a stroke and could even be used to treat damaged knees or shoulders, following successful animal trials.
“When we introduced the gel technology with the stem cells we saw huge improvement in the animals’ coordinated paw movement and overall motor function recovery,” he said.
The hydrogel technology is cost-effective and easy to manufacture on a mass scale, and it’s hoped the treatment could soon be made available in hospitals, but it must first undergo clinical trials.
“We must do our due diligence and ensure we check all the right boxes regarding safety, efficacy and regulatory approval before we can take this technology into the clinic, but we hope it can be available for use in the not-too-distant future,” Professor Parish said.

The research has been published in the journal Advanced Functional Materials.

Featured image: Professor David Nisbet © Jamie Kidston/ANU

Reference: Hunt, C. P. J., Penna, V., Gantner, C. W., Moriarty, N., Wang, Y., Franks, S., Ermine, C. M., de, I. R., Pavan, C., Long, B. M., Williams, R. J., Thompson, L. H., Nisbet, D. R., Parish 2105301, C. L., Tissue Programmed Hydrogels Functionalized with GDNF Improve Human Neural Grafts in Parkinson’s Disease. Adv. Funct. Mater. 2021, 2105301. https://doi.org/10.1002/adfm.202105301

Provided by Australian National University

Researchers ID Location on Brain Protein Linked to Parkinson’s Disease Development (Neuroscience)

Johns Hopkins Medicine researchers say they have pinpointed the section of alpha-synuclein, a protein in the brain, that causes it to latch onto brain cells called neurons and likely drives the development of Parkinson’s disease, a progressively worsening disorder that disrupts movement and neurological functions. The findings may help scientists develop a treatment that curbs the protein’s improper binding, perhaps slowing or stopping the progression of Parkinson’s.

Results of the study, conducted using cell studies and mouse neurons, were published online June 25, 2021, in the Proceedings of the National Academy of Science.

In Parkinson’s disease, the alpha-synuclein protein can misfold and take an abnormal shape, enabling it to bind and clump onto a neuron’s surface. Clumps of misfolded alpha-synuclein, known as alpha-synuclein fibrils, spread to other healthy neurons and ultimately kill these cells as the fibrils pile up.

“These findings are significant because we determined what part of alpha-synuclein fibrils is important in the binding process and how it leads to Parkinson’s progression,” says study co-author Xiaobo Mao, Ph.D., assistant professor of neurology at the Institute for Cell Engineering of the Johns Hopkins University School of Medicine.

Through several molecular and cell studies, the research team focused on a region at the tip of the misfolded alpha-synuclein fibrils called the C terminus, along with the addition of p129, a chemical group near the end of the fibril. The researchers knew from previous studies that both of these characteristics enable the fibrils to bind to neurons and cause cell death.

Mao and his Johns Hopkins Medicine colleagues — including study co-author and Parkinson’s disease researcher Ted Dawson, M.D., Ph.D., who is director of the Institute for Cell Engineering and professor of neurology at the Johns Hopkins University School of Medicine — determined the C terminus can bind receptors on the neurons due to the receptors’ positive electrical charges. When the receptors were removed, the C terminus could not clump to neurons and spread to other healthy cells.

In healthy alpha-synuclein, the C terminus is covered and cannot bind to neurons.

The researchers also investigated p129, a group of molecules in alpha-synuclein fibrils that have an extra chemical group, and are present in about 95% of people with Parkinson’s and other Lewy body neurodegenerative diseases, such as Lewy body dementia. When the alpha-synuclein fibrils with p129 and the C terminus were injected into mouse neurons, researchers found that those fibrils bound with neuron receptors and spread faster. This contributed to quicker cell death and disease progression.

To slow the progression of clumping alpha-synuclein fibrils, the researchers hope to develop treatments that target the binding process.

“If the spreading of alpha-synuclein fibrils can be blocked by preventing the C terminus from binding, it would be a good therapeutic strategy,” says Mao.

Featured image: Researchers at Johns Hopkins Medicine have pinpointed the section of a brain protein called alpha-synuclein that enables it to latch onto neurons and likely drives the development of Parkinson’s disease, a progressively worsening neurological disorder. The photomicrograph shows an aggregation of alpha synuclein in brain tissue taken from a patient with Parkinson’s disease. Credit: Public domain image courtesy of Suraj Rajan

Reference: Shengnan Zhang et al, Mechanistic basis for receptor-mediated pathological α-synuclein fibril cell-to-cell transmission in Parkinson’s disease, Proceedings of the National Academy of Sciences (2021). DOI: 10.1073/pnas.2011196118

Provided by Johns Hopkins University School of Medicine

Fruit Compound May Have Potential to Prevent And Treat Parkinson’s Disease (Neuroscience)

Johns Hopkins Medicine researchers say they have added to evidence that the compound farnesol, found naturally in herbs, and berries and other fruits, prevents and reverses brain damage linked to Parkinson’s disease in mouse studies.

The compound, used in flavorings and perfume-making, can prevent the loss of neurons that produce dopamine in the brains of mice by deactivating PARIS, a key protein involved in the disease’s progression. Loss of such neurons affects movement and cognition, leading to hallmark symptoms of Parkinson’s disease such as tremors, muscle rigidity, confusion and dementia. Farnesol’s ability to block PARIS, say the researchers, could guide development of new Parkinson’s disease interventions that specifically target this protein.

“Our experiments showed that farnesol both significantly prevented the loss of dopamine neurons and reversed behavioral deficits in mice, indicating its promise as a potential drug treatment to prevent Parkinson’s disease,” says Ted Dawson, M.D., Ph.D., director of the Johns Hopkins Institute for Cell Engineering and professor of neurology at the Johns Hopkins University School of Medicine.

Results of the new study, published July 28, in Science Translational Medicine, detail how the researchers identified farnesol’s potential by screening a large library of drugs to find those that inhibited PARIS.

In the brains of people with Parkinson’s disease, a buildup of PARIS slows down the manufacture of the protective protein PGC-1alpha. The protein shields brain cells from damaging reactive oxygen molecules that accumulate in the brain. Without PGC-1alpha, dopamine neurons die off, leading to the cognitive and physical changes associated with Parkinson’s disease.

To study whether farnesol could protect brains from the effects of PARIS accumulation, the researchers fed mice either a farnesol-supplemented diet or a regular mouse diet for one week. Then, the researchers administered pre-formed fibrils of the protein alpha-synuclein, which is associated with the effects of Parkinson’s disease in the brain.

The researchers found that the mice fed the farnesol diet performed better on a strength and coordination test designed to detect advancement of Parkinson’s disease symptoms. On average, the mice performed 100% better than mice injected with alpha-synuclein, but fed a regular diet.

When the researchers later studied brain tissue of mice in the two groups, they found that the mice fed a farnesol-supplemented diet had twice as many healthy dopamine neurons than mice not fed the farnesol-enriched diet. The farnesol-fed mice also had approximately 55% more of the protective protein PGC-1alpha in their brains than the untreated mice.

In chemical experiments, the researchers confirmed that farnesol binds to PARIS, changing the protein’s shape so that it can no longer interfere with PGC-1alpha production.

While farnesol is naturally produced, synthetic versions are used in commerce, and the amounts people get through diet is unclear. The researchers caution that safe doses of farnesol for humans have not yet been determined, and that only carefully controlled clinical trials can do so.

Though more research is needed, Dawson and his team hope farnesol can someday be used to create treatments that prevent or reverse brain damage caused by Parkinson’s disease.

Reference: Areum Jo et al., “PARIS farnesylation prevents neurodegeneration in models of Parkinson’s disease”, Science Translational Medicine  28 Jul 2021:
Vol. 13, Issue 604, eaax8891. DOI: https://doi.org/10.1126/scitranslmed.aax8891

Provided by Johns Hopkins University School of Medicine

Key Brain Region Involved in More Than Locomotion, Finding May Improve Parkinson’s Treatments (Neuroscience)

For decades, a key brain area called the mesencephalic locomotor region has been thought to merely regulate locomotion. Now, researchers in Silvia Arber’s group have shown that the region is involved in much more than walking, as it contains distinct populations of neurons that control different body movements. The findings could help to improve certain therapies for Parkinson’s disease, a neurodegenerative condition that leads to tremor, stiffness, and problems controlling different movements.

Even the mundane act of walking requires complex movements such as postural changes and the coordination of all four limbs. Scientists have known that the mesencephalic locomotor region, which is part of the midbrain, is involved in regulating walking and other forms of locomotion in many animal species. But the function of neurons in this area of the brain remained controversial.

By taking a fresh look at the mesencephalic locomotor region, researchers led by Silvia Arber, a group leader at the FMI and the Biozentrum of the University of Basel, have characterized distinct populations of neurons that are involved in movements other than walking. The findings, published in Cell, call for a rethink of the role of this key part of the midbrain. “It was surprising that within this region, which everybody has linked to locomotion, many of the neurons are not actually tuned to locomotion,” Arber says.

Working in mice, the researchers used cutting-edge techniques to label and measure the activity of different populations of excitatory neurons in the mesencephalic locomotor region. The team discovered two intermingled populations of neurons—one sending neuronal projections down to the spinal cord, and another connecting in the opposite direction to parts of a brain area called basal ganglia. The neurons connecting to the spinal cord increased their activity as the mice reared up, whereas the other population got active when the animals moved their forelimbs during behaviors such as grooming or handling objects. But only a small fraction of these neurons switched on during locomotion, the researchers found.

Next, the team used a technique called optogenetics, in which brain cells are genetically engineered to respond to light, to either activate or silence specific populations of neurons in the mesencephalic locomotor region. In a set of experiments, the researchers activated the neurons connecting to the basal ganglia as the mice moved around. As a result, the animals stopped to walk and all body movements stalled. Instead, when the researchers switched on the neurons that project to the spinal cord as the mice stood still, the animals extended their head and forelimbs forward. Only in some cases, after extending their body, the rodents started to walk. When these neurons were silenced, the researchers observed opposite behavioral responses.

Previous work from the Arber group indicates that neurons from the mesencephalic locomotor region that send their projections to an area of the brainstem called medulla are involved in the control of locomotion. The new study suggests that those that connect directly to the spinal cord are instead involved in regulating body extension and postural changes, which are likely essential for initiating locomotion.

Besides upending a long-standing idea about the role of the mesencephalic locomotor region, the study could also have implications for easing postural and gait problems in people with Parkinson’s disease who do not respond to drugs. An experimental therapy that employs a technique called deep brain stimulation—in which electrical impulses are delivered directly to the mesencephalic locomotor region of people with Parkinson’s disease—has yielded inconsistent results. While some patients reported small benefits, others experienced many side effects. Arber’s recent findings suggest why: applying electrical impulses to all neurons influences the activity of distinct neuronal populations in an uncontrolled manner. A better strategy would be to stimulate only the neurons that project to the spinal cord or the medulla, Arber says. “Therapeutic approaches that target and activate specific neurons could be very successful,” she says.

Next, the team plans to investigate the role of the mesencephalic locomotor region in action selection—a process through which the brain ‘chooses’ to perform a particular movement and inhibits conflicting motor programs. “It’s exciting that this region controls more than locomotion, so it will be interesting to understand how the neurons we identified interact with other brain regions involved in movement control,” Arber says.

Featured image: Graphical abstract. Credit: DOI: 10.1016/j.cell.2021.07.002

Reference: Manuel J. Ferreira-Pinto et al, Functional diversity for body actions in the mesencephalic locomotor region, Cell (2021). DOI: 10.1016/j.cell.2021.07.002

Provided by Friedrich Miescher Institute for Biomedical Research

Parkinson’s Disease: How Lysosomes Become A Hub For The Propagation Of The Pathology (Neuroscience)

Over the last few decades, neurodegenerative diseases became one of the top 10 global causes of death. Researchers worldwide are making a strong effort to understand neurodegenerative diseases pathogenesis, which is essential to develop efficient treatments against these incurable diseases. However, our knowledge about the basic molecular mechanisms underlying the pathogenesis of neurodegenerative diseases is still lacking. A team of researchers found out the implication of lysosomes in the spread of Parkinson’s disease.

The accumulation of misfolded protein aggregates in affected brain regions is a common hallmark shared by several neurodegenerative diseases (NDs). Mounting evidence in cellular and in animal models highlights the capability of different misfolded proteins to be transmitted and to induce the aggregation of their endogenous counterparts, this process is called “seeding”. In Parkinson’s disease, the second most common ND, misfolded α-synuclein (α-syn) proteins accumulate in fibrillar aggregates within neurons. Those accumulations are named Lewy bodies.

α-syn fibrils spreads through TNTs inside lysosomes

In 2016, a team of researchers from the Institut Pasteur (Paris) and the French National Centre for Scientific Research (in French: CNRS, Centre national de la recherche scientifique) demonstrated that α- syn fibrils spread from donor to acceptor cells through tunneling nanotubes (TNTs). They also found out that these fibrils are transferred through TNTs inside lysosomes. “TNTs are actin-based membrane channels allowing the transfer of several cellular components including organelles between distant cells. Lysosomes are organelles normally deputed to the degradation and recycling of toxic/damaged cell material” describes Chiara Zurzolo, head of the Membrane Traffic and Pathogenesis Unit at the Institut Pasteur.

α-syn fibrils can modify lysosome shape and permeability to allow seeding and diffusion

Following this original discovery, researchers, now shed some light on how lysosomes participate in the spreading of α-syn aggregates through TNTs. “By using super-resolution and electron microscopy, we found that α-syn fibrils affect the morphology of lysosomes and impair their function in neuronal cells. We demonstrated for the first time that α-syn fibrils induce the peripheral redistribution of the lysosomes thus increasing the efficiency of α-syn fibrils’ transfer to neighbouring cells,” continues Chiara Zurzolo. They also showed that α-syn fibrils can permeabilize the lysosomal membrane, impairing the degradative function of lysosomes and allowing the seeding of soluble α-syn, which occurs mainly in those lysosomes. Thus, by impairing lysosomal function α-syn fibrils block their own degradation in lysosomes, that instead become a hub for the propagation of the pathology.


This discovery contributes to the elucidation of the mechanism by which α-syn fibrils spread through TNTs, while also revealing the crucial role of lysosomes, working as a Trojan horse for both seeding and propagation of disease pathology. This information can be exploited to establish novel therapies to target these incurable diseases.


α-Synuclein fibrils subvert lysosome structure and function for the propagation of protein misfolding between cells through tunneling nanotubesPlos Biology, July 20 2021

Provided by Institut Pasteur

Tetanus Toxin Fragment May Treat Depression, Parkinson’s Disease and ALS (Neuroscience)

Depression has been treated traditionally with inhibitors of serotonin reuptake in the central nervous system. These drugs do not come without side effects, such as lack of immediate therapeutic action, the need for daily doses and the danger of becoming addicted to some of these drugs. That is why scientists continue to work on new therapies to treat depression.

In 2019, an international group of researchers co-led by Dr Yousef Tizabe from the Howard University College of Medicine in Washington, D.C., and Professor José Aguilera from the Department of Biochemistry and Molecular Biology and the Institut de Neurociències at the Universitat Autònoma de Barcelona (UAB), observed that a non-toxic derivative of the tetanus neurotoxin (which causes tetanus infections) improved depression symptoms in rat animal models. “One intramuscular dosis of Hc-TeTx made depression symptoms disappear in less than 24 hours, and its effects lasted two weeks”, explains Aguilera. Based on these findings, scientists began to work on discovering the mechanism through which this substance produces these effects.

In a recent study coordinated by Professor Aguilera and conducted in collaboration with the research group led by Dr Thomas Scior of the Benemérita Universidad Autónoma de Puebla (BUAP) in Mexico, researchers demonstrated that Hc-TeTx is capable of inhibiting the transport of serotonin within the central nervous system, by binding to neurotrophin receptors, proteins that induce the survival of neurons. These results, published in the journal Molecules, suggest that the drug may not only serve in treating depression, but also be useful in treating neurodegenerative diseases, such as Parkinson’s disease or amyotrophic lateral sclerosis (ALS).

According to researchers, the advantages of introducing Hc-TeTx as a new drug are evident. A biweekly or monthly dosis would allow medical professionals to control the progress. Since it is a recombinant product, there would be no problems with drug safety, production or high costs. Furthermore, in neurodegenerative cases, Hc-TeTx would stop the development of the pathology and at the same time eliminate any disease-related depressions.

Researchers recently patented the therapeutic use of Hc-TeTx for the treatment of depression, Parkinson’s disease and amyotrophic lateral sclerosis, and are now looking for investors to be able to conduct clinical trials on humans. “This is an important advance in science, and even more so now when in addition to the high incidence in depression and alterations in behaviours, we see mental alterations as a result of COVID-19 and the negative environments of stress, self-isolation or fear”, Aguilera concludes.

Featured image: Mice neuromuscular junction in a tibialis anterior muscle slice. Microscope images obtained for the research. © UAB

Reference: Candalija, A.; Scior, T.; Rackwitz, H.-R.; Ruiz-Castelan, J.E.; Martinez-Laguna, Y.; Aguilera, J. Interaction between a Novel Oligopeptide Fragment of the Human Neurotrophin Receptor TrkB Ectodomain D5 and the C-Terminal Fragment of Tetanus Neurotoxin. Molecules 2021, 26, 3988. https://doi.org/10.3390/molecules26133988

Provided by UAB

UCPH Researchers Prove Powerhouse Malfunction As The Major Cause Of Parkinson’s Disease (Neuroscience)

The major cause of Parkinson’s Disease is a dysregulation of immune genes central for fighting against viruses, a new study reveals. Researchers from the University of Copenhagen show that this dysregulation leads to a malfunction in the cell’s powerhouse, which cannot produce sufficient energy for neurons to stay alive, causing them to gradually die.

12,000 people in Denmark and 7 to 10 million people worldwide suffer from Parkinson’s Disease (PD). It is the second most common neurogenerative disorder of aging and the most common movement disorder, but the cause of the disease is largely unknown.

In a new study, researchers from the University of Copenhagen show that the most common form of the disease, encompassing 90 to 95 percent of all Parkinson’s Disease cases known as sporadic PD, is caused by a blockage of a pathway that regulates the nerve cell’s powerhouse, the mitochondria. 

‘Just like when people eat, cells take what they need and get rid of the rest waste products. But if our brain cells have this specific kind of signaling blockage, it means that the powerhouse of the cell – mitochondria – cannot get cleaned up after being damaged’, explains corresponding author and group leader Professor Shohreh Issazadeh-Navikas at the Biotech Research & Innovation Centre.

The blockage leads to an accumulation of high amounts of damaged mitochondria, while not being able to produce enough energy for the cells. It causes neurons to gradually die, which is the reason for the development of Parkinson’s Disease symptoms, and why it leads to dementia.

The blockage is caused by a dysregulation of the immune genes, more specifically a pathway called type 1 interferon, which is normally important for fight against viruses, but now we show that it is also responsible for regulating the energy supply of the nerve cells.

‘Every part of our body needs to be regulated. We get a signal to stop eating, when we are full, and the same thing happens everywhere else in our body. If we get an infection, parts of our body need to fight it and stop it from replicating. But when the infection is cleaned up, the signal should subside. This is the job of a protein called PIAS2. That causes the blockage of the type 1 interferon-pathway, and when the infection is over, the blockage should stop and go back to normal. But that does not seem to be the case in patients with Parkinson’s Disease. We further demonstrate that this dysregulation leads to a defect in the mitochondrial energy supply, as mentioned before’, says Shohreh Issazadeh-Navikas.

These pathways are very important for brain functions, but they are also associated with microbial and virus recognition. For example, they are very important for fighting COVID-19, and a mutation in the related gene has been shown to be linked to a deadly outcome after contracting COVID-19.

A detail look into what happens in the neurons. Illustration by authors © University of Copenhagen

Combining datasets for a bigger picture

The researchers combined and analyzed four data sets, which studied neurons from brains with Parkinson’s Disease and looked at what type of genes they express.

They then looked at which gene patterns were disturbed in patients with Parkinson’s Disease and especially those who had also developed PD with dementia.

In order to test the results, the major findings of the combined data was tried in three different mouse models using a negative regulator of the type I interferon pathway, PIAS2, which had been identified from the patients study as one of the key proteins linked to the progression of Parkinson’s Disease and dementia.

‘We show that a high accumulation of the PIAS2-protein is what is causing the blockage in the pathway, which should have activated the processes responsible for removing damaged protein and mitochondrial garbage’, says Shohreh Issazadeh-Navikas.

‘The accumulation of damaged mitochondrial mass further leads to increase of other toxic proteins. So when we compare patients to same-aged healthy patients without Parkinson’s Disease, we see that this PIAS2-protein is highly expressed in the neurons, which is why this pathway should be evaluated for potential roles in the other forms of familial Parkinson’s Disease that we have not studied here.’

The researchers hope the study will encourage research to counteract the pathway blockage, which could have a beneficial impact on the disease and towards preventing dementia.

In the next stages, the Shohreh Group will study how the pathway contributes to neuronal homeostasis and survival, as well as how its dysregulation causes neuronal cell death.

Read the full paper ‘PIAS2-mediated blockade of IFN-β signaling: a basis for sporadic Parkinson disease dementia’ here.

Featured image credit: Colourbox

Provided by University of Copenhagen

Researchers Identify an Early Neuronal Dysfunction in Parkinson’s That Could Help Early Diagnosis (Neuroscience)

  • Researchers from IDIBELL and the University of Barcelona (UB) have described that neurons derived from Parkinson’s patients show impairments in their transmission before neurodegeneration.
  • For this study, it has been used dopaminergic neurons differentiated from patient stem cells as a model.

Parkinson’s is a neurodegenerative disease characterized by the death of dopaminergic neurons. This neuronal death leads to a series of motor manifestations characteristic of the disease, such as tremors, rigidity, slowness of movement, or postural instability. In most cases, the cause of the disease is unknown, however, mutations in the LRRK2 gene are responsible for 5% of cases.

Current therapies against Parkinson’s are focus on alleviating the symptoms but do not stop its progression. It is thought that early interventions before the appearance of the first symptoms that prevent neuronal death could slow down or even stop the evolution of the disease. However, currently, the diagnosis is based on the appearance of symptoms, when 70% of the neurons have already been lost.

Dr. Antonella Consiglio (right) with work co-authors Lucas Blasco-Agell, Irene Fernández-Carasa, Meritxell Pons-Espinal, Valentina Baruffi (right-left).© IDIBELL

A group of researchers from IDIBELL and the University of Barcelona (UB), led by Dr. Antonella Consiglio (group leader at IDIBELL, ICREA Academy researcher, and professor at the Faculty of Medicine and Health Sciences of the UB and IBUB/Institute of Biomedicine of the UB), Dr. Angel Raya (coordinator of the IDIBELL Regenerative Medicine program and ICREA researcher) and Dr. Jordi Soriano (group leader and professor at the UB and the Institute of Complex Systems from the University of Barcelona), with other national and international collaborators, have identified early functional deficiencies, before death, in neurons derived from patients with genetic Parkinson’s. According to Dr. Consiglio “, these discoveries open the door to early diagnosis, which would allow us to carry out a premature intervention that would slow down neuronal death, and therefore, would stop the evolution of the disease“.

In this work, dopaminergic neurons, the most vulnerable in Parkinson’s, differentiated from stem cells (iPSC) of healthy individuals and patients with genetic Parkinson’s, have been used as a model. Researchers have observed that these dopaminergic neurons are capable of maturing and forming functional neural networks in culture, in both control and Parkinson’s disease conditions.

However, in this work published in npj Parkinson’s Disease, it is shown that neurons from individuals with Parkinson’s are more spontaneously active and present more explosion episodes in which, for example, the entire network is activated at the same time. All this before the neurodegeneration. The researchers believe that this early neuronal dysfunction could be contributing to initiating the cascade of events responsible for the death of dopaminergic neurons, and consequently, Parkinson’s disease. Furthermore, this work highlights the extraordinary window of opportunity provided by experimental models based on iPSC in the understanding and presymptomatic evaluation of neurodegenerative diseases.

This work was supported by the European Research Council-ERC, the Spanish Ministry of Economy and Competitiveness, the Carlos III Institute, AGAUR, and the CERCA program of the Generalitat de Catalunya.

Schematic of the experimental design for investigating the emergence of functional alterations in dopaminergic neurons obtained from PD patient-specific iPSC. After their generation in the plate, monitorisation of calcium intracellular levels has been used to follow the organisational changes and dynamical traits of the neuronal networks during maturation. Functional analysis of the neuronal connectivity in these cultures allowed the study of early events that originate the pathology. Gene editing in the original patient derived iPSC allowed to revert these defects. © IDIBELL

The Bellvitge Biomedical Research Institute (IDIBELL) is a biomedical research center created in 2004. It is participated by the Bellvitge University Hospital and the Viladecans Hospital of the Catalan Institute of Health, the Catalan Institute of Oncology, the University of Barcelona and the City Council of L’Hospitalet de Llobregat.

IDIBELL is a member of the Campus of International Excellence of the University of Barcelona HUBc and is part of the CERCA institution of the Generalitat de Catalunya. In 2009 it became one of the first five Spanish research centers accredited as a health research institute by the Carlos III Health Institute. In addition, it is part of the “HR Excellence in Research” program of the European Union and is a member of EATRIS and REGIC. Since 2018, IDIBELL has been an Accredited Center of the AECC Scientific Foundation (FCAECC).

Featured image: From left to right, Àngel Raya, Antonella Consiglio and Jordi Soriano © IDIBELL


Parkinson’s disease patient-specific neuronal networks carrying the LRRK2 G2019S mutation unveil early functional alterations that predate neurodegeneration. G. Carola et al. npj parkinson’s disease. 2021

Provided by IDIBELL

Human Molecule Block the Toxic Forms of the Protein Triggering Parkinson’s Disease Identified (Neuroscience)

Researchers at the UAB and the UniZar have identified a human peptide found in the brain that blocks the α-synuclein aggregates involved in Parkinson’s disease and prevents their neurotoxicity. The study, published in Nature Communications, suggests that this could be one of the organism’s natural mechanisms with which to fight aggregation. The discovery may help to develop new therapeutic and diagnosis strategies for Parkinson’s disease and other synuclein pathologies.

The death of neurons specialised in the synthesis of dopamine, one of the brain’s main neurotransmissors, deteriorates the motor and cognitive capacities of those with Parkinson’s disease. The loss of these neurons is related to alpha-synuclein aggregation. Recent studies show that oligomers, the initial aggregates of this protein, are the most pathogenic forms of α-synuclein and are responsible for the spreading of the disease in the brain.

Therefore, one of the more promising approaches in fighting this disorder consists in neutralising these oligomers and, thus, slow down the pathological progression. However, the fact that these aggregates do not present a defined structure and that they are transitory by nature makes it extremely difficult to identify molecules that bind with enough strength as to explore any clinical application.

A scientific collaboration between researchers from the Institute for Biotechnology and Biomedicine (IBB) at the Universitat Autònoma de Barcelona (UAB) and from the Instituto de Biocomputación y Física de Sistemas Complejos (BIFI) of the Universidad de Zaragoza (UniZar) now has been able to identify a human endogenous peptide which strongly and specifically attaches to the α-synuclein oligomers, thus avoiding their aggregation and blocking their neurotoxicity, two processes closely related to the neurodegenerative decline of Parkinson’s disease. The identification and study of the peptide, called LL-37, was recently published in Nature Communications.

“LL-37 interacts with the toxic alpha-synuclein oligomers in a selective manner and with a strength superior to that of any peptide previously described, equivalent to the strength exhibited by antibodies. It inhibits aggregation at very low concentrations and protects neuronal cells from being damaged”, researchers point out.

They add that, “LL-37 is found naturally in the human organism, both in the brain and in the intestine, organs in which α-synuclein aggregation takes place in Parkinson’s disease. This suggests that LL-37’s activity might respond to a mechanism developed by the body itself as a means to naturally fight this disease.”

Encouraged by this idea, researchers now want to study how its expression can be regulated and if this strategy can become a safe therapy with the potential of influencing the course of the disease. “There is a possibility that a therapy for Parkinson’s disease already lies in our interior and that it only needs to be activated correctly”, states Salvador Ventura, researcher at the IBB and coordinator of the study.

The identification of LL-37 was conducted under the framework of a research analysing the structure and characteristics of pathogenic oligomers with the aim of neutralising them in a specific manner. The analyses conducted demonstrate that helical peptides with a hydrophobic side and another positively charged side are ideal for this type of activity. The trials allowed researchers to identify three molecules with anti-aggregation activity: in addition to the human molecule, a second peptide present in bacteria and a third artificially made molecule were identified.

In addition to representing a possible therapeutic route for Parkinson’s disease and other synuclein pathologies, the molecules identified in the study are promising tools for its diagnosis, given that they discriminate between functional and toxic α-synuclein species.

“Until now there were no molecules capable of selectively and efficiently identifying toxic α-synuclein aggregates; the peptides we present on these issues are unique and, therefore, have great potential as diagnostic and prognostic tools,” says study co-coordinator Nunilo Cremades, researcher at BIFI-UniZar.

In the study, over 25,000 human peptides were computationally analysed, and single molecule spectroscopy methods, as well as protein engineering, were applied, in addition to cell cultures in vitro using toxic oligomers.

Participating in the study were researchers from the IBB-UAB and the Department of Biochemistry and Molecular Biology at the UAB Jaime Santos (first author of the article), Irantzu Pallarès and Salvador Ventura (co-coordinators of the study), members of the “Protein Folding and Conformational Diseases” group; and BIFI-UniZar researchers Pablo Gracia (second author of the article) and Nunilo Cremades (co-coordinator of the study, predoctoral researcher and lead researcher, respectively, of the “Amyloid Protein Misfolding and Aggregation” NEUROMOL group from the BIFI-Unizar.

Featured image: Schematic representation of the human peptide LL37 binding the toxic oligomers of alpha-synuclein, blocking its propagation and preventing its neurotoxicity. Author: Irantzu Pallarès (IBB)

Original article: Santos, J., Gracia, P., Navarro, S. et al. α-Helical peptidic scaffolds to target α-synuclein toxic species with nanomolar affinity. Nat Commun 12, 3752 (2021). https://doi.org/10.1038/s41467-021-24039-2

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