New Method Shows How Alpha-synuclein Can Damage Mitochondria

mitochondrial damage

A new technique shows that alpha-synuclein, the protein at the heart of Parkinson’s disease, affects cell membranes differently, based on their composition.

This discovery sheds light on how alpha-synuclein clumps known as amyloids might disrupt cellular membranes, potentially helping to design therapies that might slow or stop the process and, by extension, disease progression.

Researchers at Chalmers University of Technology, in Sweden, adapted microscopy techniques used to analyze structural changes in biological molecules to understand how amyloid-forming proteins like alpha-synuclein can disrupt cellular membranes.

Their study, “Single-vesicle imaging reveals lipid-selective and stepwise membrane disruption by monomeric alpha-synuclein,” was published in the peer-reviewed journal PNAS.

Mitochondria, membrane-enclosed structures within cells that produce energy, suffer damage over the course of Parkinson’s disease. Pathological versions of alpha-synuclein are thought to affect or even cause such damage.

To better understand this interaction, the Swedish team members investigated whether they could detect changes in membrane structure due to alpha-synuclein, which could lead to a more complete picture of the process.

The researchers generated two types of vesicles, or membrane-enclosed sacs, one of which approximated the composition of mitochondria and the other, that of synaptic vesicles, where alpha-synuclein is thought to help with release and trafficking.

Synaptic vesicles are tiny structures that store different neurotransmitters, or chemical messengers, that are then released at the synapse: the junction between two nerve cells that allows them to communicate.

The researchers then exposed these vesicles to small amounts of alpha-synuclein and monitored the resulting interactions.

Although the chemical differences in the two membranes were relatively small, alpha-synuclein had markedly different effects on each one. Alpha-synuclein attached itself to both membranes, but only deformed the mitochondrial-like membrane, causing its contents to leak out.

“In our study, we observed that alpha-synuclein binds to — and destroys — mitochondrial-like membranes, but there was no destruction of the membranes of synaptic-like vesicles,” Pernilla Wittung-Stafshede, PhD, professor of chemical biology at Chalmer University and one of the study’s authors, said in a university press release.

“The damage occurs at very low, nanomolar concentration, where the protein is only present as monomers — non-aggregated proteins,” she added. “Such low protein concentration has been hard to study before but the reactions we have detected now could be a crucial step in the course of the disease.”

An analysis of this interaction showed that to generate the observed membrane deformations, alpha-synuclein had to insert itself deeper into the mitochondria-like membrane than the synaptic vesicle-like membrane. Previously, alpha-synuclein was thought to lie flat upon the membrane surface.

This is consistent with observations that alpha-synuclein binds better to model membranes with low lipid density, high curvature, and/or those containing irregularities, such as is found in the mitochondria-like membrane.

Past studies have also reported that alpha-synuclein causes imperfections in these membranes by making them less rigid and more porous. The researchers mentioned that if alpha-synuclein binds preferentially to membranes that contain irregularities and can introduce irregularities on its own, then a small initial binding event could trigger a chain of events that leads to vesicle collapse.

This may explain why the team observed significant structural changes in response to a low number of alpha-synuclein molecules. They suggest that membrane regions with a relatively high density of alpha-synuclein molecules can make it easier for yet more molecules to attach themselves.

One of the key aspects of the team’s technique is that it enables researchers to study small numbers of molecules without the need for fluorescent markers. Fluorescent labeling is a common method for tracking specific biological molecules, but the labels themselves can affect the very reactions under study.

Having validated the utility of their technique, the researchers plan to experiment with alpha-synuclein variants and with membranes that more closely resemble those found in cells.

“We also want to perform quantitative analyses to understand, at a mechanistic level, how individual proteins gathering on the surface of the membrane can cause damage,” said Fredrik Höök, PhD, professor in the department of physics, who was also involved in the research.

“Our vision is to further refine the method so that we can study not only individual, small — 100 nanometres — lipid vesicles, but also track each protein one by one, even though they are only 1–2 nanometres in size,” he said. “That would help us reveal how small variations in properties of lipid membranes contribute to such a different response to protein binding as we now observed.”

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New Light-Controlled Tool Allows Study of Mitochondrial Damage in Live Neurons

mitochondrial damage

Scientists developed a new light-controlled tool that allows them to study the impact of mitochondrial damage in the live neurons of small transparent fish larvae, a study reports.

By allowing researchers to understand the mechanisms by which mitochondrial damage affects neurons, the new tool may potentially be used to develop new ways to restore the function of impaired neurons in patients with Parkinson’s, Alzheimer’s, and other neurodegenerative disorders.

The study, “Chemoptogenetic ablation of neuronal mitochondria in vivo with spatiotemporal precision and controllable severity,” was published in the journal eLife.

Defects in mitochondria — the cell compartments responsible for the production of energy — found inside neurons have been linked to several neurodegenerative diseases. For instance, in patients with Parkinson’s or Alzheimer’s disease, studies have shown that dying neurons often have signs of mitochondria damage.

However, the exact mechanisms by which dysfunctional or damaged mitochondria contribute to neuronal death are still unclear. Technical challenges are part of the reason why research into this field has not yet advanced further.

“Gaining a better understanding of this process requires studying the impact of mitochondrial damage in live neurons, something that is still difficult to do,” the researchers wrote.

However, a team of scientists at the University of Pittsburgh may have found a way to overcome this limitation by using genetically modified transparent fish larvae along with a newly developed light-controlled tool that can be used to damage mitochondria found inside neurons.

They used fish larvae that had been genetically engineered to produce a protein called dL5 in mitochondria found inside their neurons, which can interact with a chemical compound called MG2I. When attached to each other and exposed to far-red light, dL5 and MG2I respond by producing reactive oxygen species (ROS) that trigger oxidative stress that damages mitochondria.

Oxidative stress is a type of cell damage caused by high levels of oxidant molecules, or ROS.

This means that each time fish larvae were exposed to far-red light, the mitochondria found inside their neurons were injured in a way that was directly proportional to the intensity of the light used.

“The really big first here is that we’ve got a way of targeting a one micrometer component of specific cells in a whole animal, with absolute precision in terms of where and when the damage happens and how much damage there is,” Edward Burton, MD, PhD, the lead author of the study, said in a news story.

“Compare that to coarser techniques, such as adding chemicals to the zebrafish’s water — there’s no way to control which cells get damaged,” added Burton, who is an associate professor of neurology at the University of Pittsburgh and a neurologist at the University of Pittsburgh Medical Center.

Using this system, the researchers observed that each time they exposed fish larvae to far-red light, they were no longer able to swim.

When they examined mitochondria found inside the animals’ neurons, they found they had swollen and lost their typical membrane ruffles where the production of adenosine triphosphate (ATP) — the small molecule used by cells as “fuel” — takes place.

Without ATP to sustain their needs, the neurons lost the ability to communicate with each other, and eventually started to die approximately 24 hours after the fish larvae had been exposed to far-red light.

“This new light-controlled tool could help to understand the consequences of mitochondrial damage, potentially revealing new ways to rescue impaired neurons in patients with Parkinson’s or Alzheimer’s disease,” the researchers wrote.

They have already created new genetically modified animals where dL5 is only produced in dopaminergic neurons — those that are lost over the course of Parkinson’s — which they hope will allow them to map the biochemical events leading up to neurodegeneration in Parkinson’s.

The new tool could also be used in other cell types to block the function of other cell compartments and study different types of disease.

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New Parkinson’s Treatment Target – Drp1 Protein Linked to Sense of Smell – Found in Rat Model, Study Reports

Drp1 Protein Sense of Smell

A new potential target for treating Parkinson’s, a protein named Drp1, has been identified using a rat model of the disease, a study reported.

The target was found to play a central role in the underlying cause of the degeneration and inflammation of nerve cells in the olfactory bulb, the area responsible for the sense of smell. Losing the sense of smell is an early symptom of the progressive neurodegenerative disease. 

The study, “Drp1, a potential therapeutic target for Parkinson’s disease, is involved in olfactory bulb pathological alteration in the Rotenone-induced rat model,” was published in the journal Toxicology Letters.

One early non-motor symptom of Parkinson’s is a loss of the sense of smell. Before it appears in the brain, the toxic buildup of the protein alpha-synuclein — a hallmark of the condition — occurs in the olfactory bulb, which is the the neural structure located above the sinuses that’s responsible for the ability to smell. 

However, the underlying mechanism that leads to early-stage olfactory bulb impairment is unclear.

A common phenomenon in Parkinson’s is the improper functioning of the mitochondria, or the small structures within the cell that produce energy — the cells’ powerhouses. A protein called dynamin-related protein 1 (Drp1) regulates mitochondria dynamics, notably in the cell division process. Chemicals that target this protein have been shown to cause mitochondrial fragmentation leading to the loss of neurons. 

Mitochondrial fragmentation also is known to drive a pro-inflammatory response, a common characteristic of neurodegenerative diseases. 

This prompted researchers to investigate whether Drp1-mediated mitochondrial damage played a role in the impairment of the olfactory bulb. The team used a rat model in which Parkinson-like symptoms were induced by the infusion of rotenone, a mitochondria inhibitor.

To examine the effects of rotenone on the olfactory bulb, a group of rats were treated and compared with a group of untreated rats. In a second experiment, these two groups of animals were compared with a third group treated with a specific Drp1 inhibitor.

Compared with the untreated group, rats treated with rotenone lost more weight and displayed parkinsonian features such as poor motor coordination. The treated rats also had a characteristic depletion of dopamine — the chemical messenger or neurotransmitter produced by dopaminergic neurons that are progressively lost in Parkinson’s disease.

An examination of olfactory tissue under the microscope showed that the density of dopamine-producing neurons was significantly reduced in rotenone-treated rats compared with the untreated group. 

Rotenone triggered the activation of olfactory-specific astrocytes — star-shaped neuroglia or neural support cells — and microglia, a type of brain-specific immune cell. The accumulation of these cells was accompanied by a significant increase in the production of pro-inflammatory markers. 

An examination of the mitochondria in the control animals found typical rod-like shapes characteristic of healthy olfactory cells. In contrast, large numbers of mitochondria in the rotenone-treated group were small and damaged. 

Rotenone injection also caused a dramatic reduction of Drp1 outside of the mitochondria and a significant increase on the inside. 

Finally, the researchers found that adding a Drp1 inhibitor led to a significant reduction in the loss of dopaminergic neurons, increased the presence of healthy mitochondria, and blocked the production of pro-inflammatory markers. 

“In summary, the present findings demonstrate that Drp1-mediated mitochondrial fragmentation induced by rotenone injection participated in neuropathologic changes in the olfactory bulb,” the researchers concluded. 

They said further study needs to be done “to elucidate the network as well as focus on the aberrant mitochondrial dynamics to explore the mechanism.”

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New Cellular Model Can Reconstruct Entire Process of Lewy Body Formation in Parkinson’s Disease, Study Says

Lewy body formation, Parkinson's

Scientists have developed a new cellular model that can help reconstruct the entire process of Lewy body formation — a key event that underlies neurodegeneration in Parkinson’s disease — and that could potentially be used to evaluate the effect of therapeutics on the toxic protein buildup observed during this process.

The study, “The process of Lewy body formation, rather than simply α-synuclein fibrillization, is one of the major drivers of neurodegeneration,” was published in PNAS.

Parkinson’s is a multisystem neurodegenerative disorder with motor and non-motor features caused by the death of midbrain dopamine-producing neurons. These nerve cells are thought to die as a consequence of the aggregation, or clumping together, of a protein called alpha-synuclein in small fiber-like, or insoluble fibril, structures known as Lewy bodies.

Although evidence indicates abnormal alpha-synuclein accumulation is essential for the development of Parkinson’s disease, not much is known about the molecular and cellular processes that control the transformation of healthy alpha-synuclein protein into insoluble fibrils and, consequently, their clumping into Lewy bodies.

To better understand these biological events at a genetic, molecular, biochemical, structural, and cellular level, researchers at the Brain Mind Institute in Lausanne, Switzerland, tracked the development of Lewy bodies from beginning to end.

They began by using mouse primary neurons grown in lab dishes. They then added a small amount of alpha-synuclein fibrils that would be used as “seeds” that grew by recruiting neuron-produced alpha-synuclein.

“This approach has proven incredibly useful in modeling the formation of alpha-synuclein aggregates linked to diseases like Parkinson’s,” study senior author Hilal Lashuel, PhD, said in a press release.

Scientists usually monitor cell cultures for two weeks, but Lashuel’s team decided to go beyond that time limit. Twenty-one days after seeding, the team observed Lewy body-like inclusions in approximately 22% of the neurons.

These lab-grown Parkinson’s-related structures shared between 15%-20% of their protein content with “natural” Lewy bodies, which, given the slower growth rate in the laboratory versus the human brain, is an encouraging finding.

Importantly, the Lewy-body-like clump structures had not appeared by the usual two-week cutoff point, highlighting the need to prolong the experiments to observe features characteristic of neurodegeneration.

“Time, being patient and using a swiss army knife analytical approach is all that was required,” Lashuel said.

The formation of Lewy bodies involved a complex interplay between alpha-synuclein fibrillization, protein modifications, and interactions between alpha-synuclein clumps and membranous organelles, including mitochondria, which produce energy for cells.

In addition, the researchers found that Lewy body formation — rather than simply alpha-synuclein fibril accumulation — were the major drivers of neurodegeneration, since these structures disrupted cellular functions such as energy production, and compromised nerve cell communication by changing the properties of synapses, or the junctions between nerve cells that allows them to communicate.

Formation of Lewy bodies does not occur simply through the continued formation, growth, and assembly of alpha-synuclein fibrils “but instead arises as a result of complex [alpha-synuclein] aggregation-dependent events that involve the active recruitment and sequestration of proteins and organelles over time,” the researchers wrote.

“Our results generally agree with recent findings reported on Lewy bodies from Parkinson’s disease brains,” Lashuel said. “But while previous studies only offered snapshots of fibril evolution, our model can reconstruct the entire process of Lewy body formation, making it a powerful platform for elucidating the relationship between fibrillization and neurodegeneration in Parkinson’s and other diseases, and to screen for novel potentially disease modifying therapies.”

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Light-activated Protein Used to Improve Mitochondrial Function, Reduce Parkinson’s Symptoms in Fly Study

light-activated protein improves mitochondrial function

Using a light-activated protein to improve the function of mitochondria — cells’ powerhouses— could be a therapeutic strategy for Parkinson’s disease (PD), a new study done in flies suggests.

The results of the study, “Light-driven activation of mitochondrial proton-motive force improves motor behaviors in a Drosophila model of Parkinson’s disease,” were published in Communications Biology.

Mitochondria are organelles —specialized structures within a cell — that play a number of important biological roles within cells. Their most crucial function is generating adenosine triphosphate (ATP), which is the “energy currency” of the cell that fuels other cellular processes. The incorrect functioning of these organelles has been implicated in the development of Parkinson’s.

In particular, mutations in the gene that encodes the mitochondrial protein CHCHD2 — coiled-coil-helix-coiled-coil-helix domain containing 2 — have been shown to cause early-onset PD, as well as to impair the function of the mitochondria, specifically reducing the production of ATP. Flies lacking CHCHD2 also show PD-like symptoms, such as impaired motor abilities, aggregation or buildup of alpha-synuclein protein, and death of dopamine-producing (dopaminergic) neurons.

Normally, mitochondria create ATP using energy stored in the chemical bonds that are in the molecules of the food people eat. In the new study, the researchers created flies that got their energy a different way: from light.

Mitochondria generate ATP by moving hydrogen ions, or protons, across their membranes, which are their outer barrier layers. This creates a protonmotive force (delta p or Δp), which is what ultimately drives ATP generation.

The researchers created flies that had a protein called delta-rhodopsin (dR) on their mitochondrial membranes. dR is a protein originally found in archaea — single-celled organisms — that live in extremely high-salt conditions. This protein acts as a proton pump that basically can move protons across cellular membranes, such as the mitochondrial membrane. However, instead of getting its energy from food, dR moves protons using energy from particular wavelengths of light.

“Light-activated dR increases Δp, which promotes ATP production,” the researchers said.

The team tested whether light-activated dR could be used to rescue mitochondrial activity in flies lacking CHCHD2.

They found that, as expected, flies lacking CHCHD2 produced significantly less ATP than wild-type flies at 30 days of age. In flies with dR on their mitochondria, this also was the case when there was no dR-activating light. When that light was provided, however, the flies produced an amount of ATP that was not significantly different from the amount generated in wild-type flies.

Flies with light-activated dR also had lower levels of reactive oxygen species, highly reactive molecules that can damage cellular structures and are generated by the normal functioning of mitochondria. These flies also had lower levels of alpha-synuclein, a key protein that builds up in the brain in Parkinson’s disease. Flies with light-activated dR also had more surviving dopaminergic neurons — nerve cells that are progressively lost in Parkinson’s.

Additional experiments using a non-functional version of dR confirmed that these effects were a result of the protein itself, not some unforeseen non-specific effect of light on mitochondria.

“In conclusion,” the researchers said, “this study provides ‘proof of concept’ that Δp maintenance is beneficial for neuroprotection and that the development of proton pumps driven by optogenetic [light-driven] or pharmacogenetic [drug-driven] techniques is a potential therapeutic strategy for PD.”

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Compound That Protects Mitochondria May Be Possible Therapy Candidate for Parkinson’s, Study Suggests

Miro1, Parkinson's

A small molecule that can protect the function of mitochondria — known as the powerhouses of cells — and prevent cell death can also prevent brain damage in a rodent stroke model, highlighting its potential as a possible therapeutic candidate for neurodegenerative disorders such as Parkinson’s disease, a study has found.

The results were published in an article, “A small molecule protects mitochondrial integrity by inhibiting mTOR activity,” in the Proceedings of the National Academy of Sciences.

Although the exact trigger for Parkinson’s disease remains to be identified, research indicates that its causative mechanism involves genetics, problems in the mitochondria, and oxidative stress — an imbalance between the production of harmful free radicals and the ability of cells to detoxify, which results in cellular damage.

Taken together, these molecular and cellular changes eventually lead to the death of dopamine-producing neurons, the type of nerve cell that is gradually lost in Parkinson’s disease.

Mitochondrial dysfunction can lead to many diseases including neurodegenerative ones. Damage in the cell’s powerhouse triggers a natural process inside the cell, known as apoptosis (or programmed cell death), with the ultimate goal of killing that same cell.

Using a lab model that mimicked the activation of damaged mitochondria-induced apoptosis, researchers at Tsinghua University, in China, were able to screen and identify compounds that could block cellular death by protecting mitochondrial integrity and function.

One small molecule, which scientists called compound R6, was found to block apoptosis by inhibiting the release of cytochrome c and protect both mitochondrial integrity and function.

Cytochrome c is a protein that is released by the mitochondria and initiates apoptosis following the reception of an apoptotic stimulus, functioning like a “go” signal for the cell to initiate its own destruction.

In addition to inhibiting the release of cytochrome c, Compound R6 also prevented apoptosis by inhibiting another major cellular signalling pathway, called mTOR. This induced the activation of autophagy, a process by which the cell removes unnecessary or dysfunctional components and, in contrast to apoptosis, does not result in cell death.

Scientists then tested Compound R6’s therapeutic potential in a rat model of stroke. A stroke occurs when a blood vessel that carries oxygen and nutrients to the brain is blocked by a clot or it bursts. As a result, the part of the brain that is irrigated by that vessel cannot get the blood (and oxygen) it needs, resulting in the death of nerve cells.

Compound R6 was able to cross the blood-brain barrier after being administered via an intraperitoneal (through the abdominal wall) injection. The blood-brain barrier is a semipermeable membrane that protects the brain against the external environment, and is a major barrier for the efficient delivery of certain therapeutics that need to reach the brain and central nervous system.

Animals that were given Compound R6 showed significantly less neuronal injury than rats without such pre-treatment after a stroke was induced in them. These neuroprotective effects were dose-dependent, with higher (25 mg/kg ) doses having a bigger protective effect than smaller ones (12.5 mg/kg).

“Given increasing appreciation that mitochondrial damage affects the etiology [cause] of several common and devastating neurodegenerative diseases, Compound R6’s ability to pass the blood-brain barrier and confer strong anti-apoptotic effects should encourage preclinical and medicinal chemistry research efforts, perhaps even extending (…) into evaluation of possible anti-aging effects,” the researchers wrote.

Compound R6’s molecular and cellular benefits make it a promising potential therapeutic candidate for age-related diseases, such as stroke and Parkinson’s, where mitochondrial damage plays a key role, the researchers said.

This is not the first time that they have found a molecule able to block cell death. Three years ago, they found a molecule, named Compound A, that could halt the death of dopamine-producing neurons by a different mechanism than that of R6, in a rat model of Parkinson’s disease.

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Parkinson’s Foundation Grants $250K for Parkinson’s UK Treatment Project

Parkinson’s Foundation

As part of a new partnership with Parkinson’s UK, the Parkinson’s Foundation has granted the nonprofit $250,000 toward a prospective new treatment linked to mitochondrial function that is being developed in the Parkinson’s Virtual Biotech program.

The grant will help advance a project aimed at uncovering new methods of potentially impeding brain cell death through stabilization of the source of energy necessary for cell survival — the mitochondria. It’s the first international funding for the Parkinson’s UK-led program and marks the beginning of a collaborative effort to move forward promising Parkinson’s (PD) treatment research.

“We are pleased to partner with Parkinson’s UK to further innovative research that will help the international PD community,” John Lehr, president and CEO of the Parkinson’s Foundation, said in a press release. “This collaboration will help us better serve people living with Parkinson’s today while furthering the promise of a cure tomorrow.”

Parkinson’s UK and its supporters and collaborators each year invest more than $5 million in Parkinson’s Virtual Biotech — the organization’s drug discovery and development arm — focusing on projects with the potential to transform patients’ lives. Fueled by project-specific partnerships with some of the world’s top research organizations, the program’s goal is to invest $29 million by the end of 2021.

“We are delighted to receive this investment from the Parkinson’s Foundation to support a growing portfolio of projects in our Virtual Biotech,” said Steve Ford, chief executive of Parkinson’s UK. “While we have made huge strides in our research efforts, we have long recognized that we can’t do it alone. The Parkinson’s Foundation shares this philosophy that we’re better together, and their investment marks a new chapter that will help ensure the Parkinson’s community receives the new treatments it needs.”

With its grant, the Parkinson’s Foundation is focusing on a £98,000 (about $126,000) year-long project with the University of Sheffield that began in August called “Novel Mitochondrial Rescue Compounds.”

Through compound modification, scientists will seek to discover and develop a potential therapy that could protect the dopamine-producing brain cells affected by Parkinson’s. The hope is that the most promising study compound ultimately will result in prospective brain cell-protecting treatments that could slow PD progression and enhance patients’ lives.

Parkinson’s is caused by the death or malfunction of dopaminergic neurons, which regulate muscle movement and coordination. To do their job, these nerve cells require large amounts of mitochondra-provided energy. Studies have widely suggested that mitochondrial dysfunction plays a central role in the development of PD.

To date, the Parkinson’s Virtual Biotech program has invested in seven drug discovery and development projects.

In addition to this collaboration, the two PD organizations also are working together on Parkinson’s Revolution, an indoor cycling fundraiser slated for Feb. 8 across the United States, the United Kingdom and Canada. The event is designed to highlight the benefits of exercise in PD while also raising funds for research and programs.

Since 1957, the Parkinson’s Foundation has invested more than $353 million in PD research and clinical care. Parkinson’s UK is Europe’s largest charitable funder of Parkinson’s research.

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Scientists Identify Potential Biomarker That Could Open New Avenues for Parkinson’s Treatment

Miro1, Parkinson's

Researchers have found a compound that can rescue dopaminergic neurons from cell death and improve locomotor activity in fly models of Parkinson’s disease.

Their findings were published in a study, “Miro1 Marks Parkinson’s Disease Subset and Miro1 Reducer Rescues Neuron Loss in Parkinson’s Models,” in the journal Cell Metabolism.

The identification of reliable molecular biomarkers that can distinguish Parkinson’s from other conditions, monitor disease progression, or provide insight about a patient’s response to a given therapeutic intervention would be groundbreaking in the field of Parkinson’s research.

Evidence indicates that dysfunctional mitochondria — i.e. the powerhouses of cells — may be a causative mechanism behind this neurodegenerative disorder. When mitochondria are dysfunctional, the body eliminates them through a process called mitophagy, whereby mitochondria are sent to cellular compartments called lysosomes, the cell’s so-called “recycling center.”

A series of proteins direct damaged mitochondria to lysosomes. For mitochondria to be recycled, these same proteins must remove Miro1, a protein found on the outer membrane of mitochondria that attaches them to the cells’ cytoskeleton. Miro1 has been linked to multiple Parkinson’s-causing genes.

Like the skeletal system, the cytoskeleton offers structural support, helps cells move around, and enables the transport of molecules and organelles, including mitochondria, inside cells.

In Parkinson’s, cells are not able to remove Miro1 from mitochondria, which then don’t get to be recycled and end up becoming toxic and eventually killing the cell — contributing to neurodegeneration.

Stanford University researchers investigated the clinical utility of Miro1 for detecting Parkinson’s and its potential in developing treatment strategies.

The scientists reproduced in the laboratory the biochemical process that leads to mitochondria degradation. They did so in skin fibroblasts from 71 Parkinson’s patients, three at-risk subjects, 10 individuals with other neurological disorders including Huntington’s disease and Alzheimer’s, and 12 healthy controls; all patients were included in the National Institute of Neurological Disorders and Stroke and the Parkinson’s Progression Markers Initiative cell repositories.

Results revealed 94% of Parkinson’s fibroblasts could not remove Miro1 from mitochondria, but cells from the controls and patients with other movement disorders had no trouble doing so. This Miro1 defect was also observed in all of the at-risk subjects.

“We’ve identified a molecular marker that could allow doctors to diagnose Parkinson’s accurately, early and in a clinically practical way,” Xinnan Wang, MD, PhD, associate professor of neurosurgery and lead author of the study, said in a news release.

“This marker could be used to assess drug candidates’ capacity to counter the defect and stall the disease’s progression,” Wang added.

Using artificial intelligence, the scientists screened 6,835,320 commercialized small molecules, all of which were able to bind in some way to the Miro1 protein. Their analysis showed four of these molecules were non-toxic, orally available, able to cross the blood-brain barrier, and would significantly reduce Miro1 levels in fruit flies by facilitating its separation from mitochondria.

One of these four tested compounds, which scientists called a “Miro1 reducer,” was then used to treat fibroblasts from a patient with Parkinson’s of unknown cause (also known as idiopathic). The compound improved Miro1 “detachment” in damaged mitochondria within these cells.

Three distinct fruit-fly strains modelling Parkinson’s-like symptoms were fed the Miro1 reducer for their entire life span (around 90 days). The compound showed no toxicity towards the animals’ physiology, prevented dopaminergic neuronal death in all fly models, and rescued locomotor deficits in two of these models.

“Our hope,” Wang said, “is that if this compound or a similar one proves nontoxic and efficacious and we can give it, like a statin drug, to people who’ve tested positive for the Miro-removal defect but don’t yet have Parkinson’s symptoms, they’ll never get it.”

Stanford’s Office of Technology Licensing has filed a provisional patent for the use of the Miro1 reducer in Parkinson’s and other neurodegenerative diseases. Wang has formed a company called CuraX to speed up the molecule’s development.

“Our results indicate that tracking this Miro1 marker and engaging in Miro1-based therapies could open new avenues to personalized medicine,” the researchers said.

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CRISPR/Cas9’s Potential in Better Understanding and Treating Parkinson’s Focus of Review Study

gene editing and disease

In a recent review, scientists highlight the potential of gene editing technologies like CRISPR/Cas9 to not only understand the molecular mechanisms behind Parkinson’s disease, but also identify new targets for treatment.

The review study, “Interrogating Parkinson’s disease associated redox targets: Potential application of CRISPR editing,” was published in the journal Free Radical Biology and Medicine.

One of the hallmarks of PD is the loss of dopamine-producing neurons in the substantia nigra — a brain region involved in the control of voluntary movements, and one of the most affected in PD. This occurs due to the clustering of a protein called alpha-synuclein in structures commonly known as Lewy bodies inside neurons.

Parkinson’s is complex and multifactorial disease, with both genetic and environmental factors playing a role in either triggering or exacerbating the disease.

Genetic causes can explain 10% of all cases of PD —  called familial PD –, meaning that in the majority of the cases (sporadic PD) there is an interplay between genetics and environmental risk factors.

Researchers at Sechenov University in Russia and the University of Pittsburgh reviewed the role of metabolic pathways, especially problems with mitochondria — cells’ powerhouses — and iron accumulation, as well as mechanisms in cell death (called apoptosis and ferroptosis) in the development and progression of Parkinson’s disease.

These processes were discussed in the context of genome editing technologies, namely CRISPR/Cas9 — a technique that allows scientists to edit genomes, inserting or deleting DNA sequences, with precision, efficiency and flexibility.

“Empirical research has established many potential metabolic abnormalities that may represent the specific key mechanisms of PD pathogenesis. However, the diversity of these findings and the lack in understanding the connections between them slow down the progress in the development of specific treatments,” the researchers wrote. These abnormalities may be “[a]mong [the] many potentially important targets for CRISPR/Cas9 based research.”

“CRISPR is a promising technology, a strategy to find new effective treatments to neurodegenerative diseases,” Margarita Artyukhova, a student at the Institute for Regenerative Medicine at Sechenov and the study first author, said in a press release.

Mitochondria don’t work as they should in people with PD, resulting in shortages of cellular energy that cause neurons to fail and ultimately die, particularly dopamine-producing neurons. Faulty mitochondria are also linked to the abnormal production of reactive oxygen species, leading to oxidative stress — an imbalance between the production of free radicals and the ability of cells to detoxify them— that also damages cells over time.  

Because mitochondrial dysfunction is harmful, damaged mitochondria are usually eliminated (literally, consumed and expelled) in a process called mitophagy — an important cleansing process in which two genes, called PINK1 and PRKN, play crucial roles. Harmful changes in mitophagy regulation is linked with neurodegeneration in Parkinson’s.

Previous studies with animal models carrying mutations in the PINK1 and PRKN genes showed that these animals developed typical features of PD – mitochondrial dysfunction, muscle degeneration, and a marked loss of dopamine-producing neurons.

PINK1 codes for an enzyme that protects brain cells against oxidative stress, while PRKN codes for a protein called parkin. Both are essential for proper mitochondrial function and recycling by mitophagy. Mutations in both the PINK1 and PRKN gene have been linked with early-onset PD.

However, new research suggests that the role of PINK1 and PRKN in Parkinson’s could be more complex and involve other genes — like PARK7  (DJ-1), SNCA (alpha-synuclein) and FBXO7  — as well as a fat molecule called cardiolipin.

CRISPR/Cas9 genome editing technology may be used to help assess the role of different genetic players in Parkinson’s disease, and to look for unknown genes associated with disease progression and development. Moreover, this technology can help generate animal and cellular models that might help scientists decipher the role of certain proteins in Parkinson’s and discover potential new treatment targets.

Iron is another important metabolic cue in Parkinson’s. While it’s essential for normal physiological functions, excessive levels of iron can be toxic and lead to the death of dopamine-producing neurons in the substantia nigra.

Iron may also interact with dopamine, promoting the production of toxic molecules that damage mitochondria and cause alpha-synuclein buildup within neurons.

CRISPR/Cas9 technology can be used to help dissect the role of proteins involved in iron transport inside neurons, which in turn may aid in designing therapies to restore iron levels to normal in the context of Parkinson’s disease.

Finally, researchers summarized evidence related to the role of two cell death pathways — ferroptosis and apoptosis — in PD. Ferroptosis is an iron-dependent cell death mechanism by which iron changes fat (lipid) molecules, turning them toxic to neurons. This process has been implicated in cell death associated with degenerative diseases like Parkinson’s, and drugs that work to inhibit ferroptosis have shown an ability to halt neurodegeneration in animal models of the disease.

Apoptosis refers to a “programmed” cell death mechanism, as opposed to cell death caused by injury. Both apoptosis and ferroptosis speed the death of dopaminergic neurons.

CRISPR/Cas9 may help to pinpoint the key players in cell death that promote the loss of  dopaminergic neurons in Parkinson’s disease, while understanding the array of proteins that are involved in these processes.

“These insights into the mechanisms of PD pathology [disease mechanisms] may be used for the identification of new targets for therapeutic interventions and innovative approaches to genome editing, including CRISPR/Cas9,” the researchers wrote.

Genome editing technology is currently being used in clinical trials to treat patients with late-stage cancers and inherited blood disorders, Artyukhova notes in the release.

These “studies allow us to see vast potential of genome editing as a therapeutic strategy. It’s hard not to be thrilled and excited when you understand that progress of genome editing technologies can completely change our understanding of treatment of Parkinson’s disease and other neurodegenerative disorders,” she adds.

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Parkinson’s UK Awards Scientist £100,000 to ID Ways of Protecting Dopamine-producing Neurons

Parkinson's UK grant

A scientist at the University of Sheffield in England has been awarded a £100,000 grant by Parkinson’s UK to develop a treatment that might slow or stop the progression of Parkinson’s disease and protect brain cells.

The one-year grant, worth about $120,000, was given to Heather Mortiboys, a senior research fellow at the university’s Institute for Translational Neuroscience (SITraN), by Parkinson’s Virtual Biotech Programme, the British charity’s therapeutic development arm.

“All the clinical treatments for people living with Parkinson’s at the moment are based on easing these sometimes devastating symptoms,” Mortiboys said in a press release. “With this new funding award … we have the potential to go on to develop a drug treatment which will actively address the root cause of these symptoms to slow, or halt the progression of Parkinson’s for the first time.”

Mitochondria, power factories for cells that include dopamine-producing brain cells, don’t work as they should in people with Parkinson’s disease.  Resulting shortages in cellular energy cause neurons to fail and ultimately die, particularly dopamine neurons. Those nerve cells are responsible for movement and coordination, and rely on mitochondria to function.

In her previous work, Mortiboys developed a model of dopamine brain cells — using skin cells from patients — that allows researchers to test potential therapies. Her research team was able to grow high numbers of brain cells derived from these skin cells. They used them to identify compounds that support dopamine neurons and their mitochondrial function, and potentially lessen cell death.

With this award, Mortiboys and her team will try to pinpoint the molecules in these compounds that are of greatest benefit to mitochondria in producing the energy needed to support these brain cells. Working in collaboration with the National Institute of Health Research (NIHR) Sheffield Biomedical Research Centre, the scientists will then move the molecules into a drug discovery phase.

“There is an urgent need for treatments to protect the nerve cells that become damaged in patients with Parkinson’s disease, which will have a crucial impact in slowing the progression of the condition and improving the quality of life” said Pamela Shaw, director of SITraN and and the university’s new Neuroscience Institute.

Potential treatments identified through this process will be further developed through a partnership with the NIHR Biomedical Research Centre at the Royal Hallamshire Hospital, a Sheffield teaching hospital, Shaw said, adding “[w]e are hugely grateful to Parkinson’s UK for supporting this important translational research.”

“We are delighted to partner and work with Dr Heather Mortiboys and her team at the University of Sheffield. Through our Virtual Biotech initiative, we are committed to accelerating promising and breakthrough treatments for Parkinson’s,” said Richard Morphy, drug discovery manager at Parkinson’s UK.

“This is an exciting new approach that could rescue defective mitochondria inside neurons to prevent dysfunction and degeneration of dopamine-producing brain cells,” Morphy said.

Parkinson’s UK, which invests about $4.8 million a year in work that advances potential treatments, estimates that about 148,000 people in the U.K. have this neurodegenerative disease.

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