Alpha-Synuclein Protein Works to Repair Damage to Cell’s DNA, Study Suggests

alpha-synuclein and DNA repair

Contrary to current knowledge, alpha-synuclein protein — whose toxic form is responsible for the formation of Lewy bodies — may play a crucial role in preventing cell death by repairing damaged DNA, a study has found.

This critical function of the protein may also be lost in Parkinson’s patients, its researchers said.

The study, “Alpha-synuclein is a DNA binding protein that modulates DNA repair with implications for Lewy body disorders,” was published in Scientific Reports.

Parkinson’s is marked by a buildup in the brain of the alpha-synuclein protein, which forms clumps known as Lewy bodies that damage and kill neurons (nerve cells). These protein inclusions are found in the cell’s cytoplasm — the jelly-like fluid that fills a cell.

Although it remains unclear how cytoplasmic aggregation of alpha-synuclein into Lewy bodies contributes to neuronal death, alpha-synuclein has also been found in the cell’s nucleus, where DNA is located and where important DNA repair mechanisms take place.

Researchers at the Oregon Health & Science University had previously shown that the formation of Lewy bodies coincided with the loss of soluble alpha-synuclein from both the cytoplasm and nucleus of mouse neurons with aggregates (clumps) in them.

“This suggests that cytoplasmic alpha-synuclein aggregation may decrease the amount of protein available for any nuclear or cytoplasmic role it may play,” the researchers wrote.

The same team now investigated whether alpha-synuclein could be involved in the DNA damage response.

Alpha-synuclein was found in the same cellular sites as DNA damage response components in both human and mouse brain cells.

DNA damage was then chemically induced in human cells that lacked alpha-synuclein. Researchers reported finding higher rates of DNA damage (what they called “double-strand breaks”) compared to alpha-synuclein-bearing cells. Likewise, mice without alpha-synuclein had increased neuronal DNA damage, which was rescued by reintroducing the human form of alpha-synuclein.

Importantly, mouse and human neurons with Lewy bodies had increased levels of DNA damage.

Scientists also observed that normal (i.e., non-toxic) alpha-synuclein is rapidly recruited to DNA damage sites and helps to repair harm by binding to the DNA molecule and facilitating a repairing reaction; more specifically, this process is called the non-homologous end-joining reaction.

Besides its known toxic role in Parkinson’s, findings suggest alpha-synuclein may have an important function in the cell nucleus, that of regulating DNA repair. They also suggest that such function is compromised in Lewy inclusion-bearing neurons, which, in turn, contributes to cell death.

“This is the first time that anyone has discovered one of its [alpha-synuclein’s] functions is DNA repair,” Vivek Unni, MD, PhD, an associate professor of neurology in the OHSU School of Medicine and senior author of the study, said in a news release.

“That’s critical for cell survival, and it appears to be a function that’s lost in Parkinson’s disease,” Unni added.

“Based on these data, we propose a model whereby cytoplasmic aggregation of alpha-synuclein reduces its nuclear levels, increases DSBs [double-strand breaks], and may contribute to programmed cell death via nuclear loss-of-function. This model could inform development of new treatments for Lewy body disorders by targeting alpha-synuclein-mediated DNA repair mechanisms,” the team concluded.

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Protein Called MITOL Linked to Parkinson’s, Research Suggests

MITOL research

Parkinson’s disease-related protein Parkin may rely on another protein called MITOL to repair damaged mitochondria, the small organelles that provide energy to cells and, when defective, can damage brain nerve cells.

Understanding these molecular mechanisms may help improve Parkinson’s therapies that intend to boost Parkin activity.

The study with this finding, “Parkin recruitment to impaired mitochondria for nonselective ubiquitylation is facilitated by MITOL” was published in the Journal of Biological Chemistry.

In a healthy brain, Parkin helps to keep cells alive and reduces the risk of harmful inflammation by repairing damage to mitochondria, which are cells’ “powerhouses.”

Parkin is an enzyme that works by “tagging” damaged mitochondrial proteins for degradation (death) by adding a molecule known as ubiquitin. Ubiquitin is part of a “quality control” system by which cells dispose of damaged, misshapen, or excess proteins.

Parkin’s activity is decreased or absent in many Parkinson’s patients, meaning that damaged mitochondria do not get repaired by Parkin and start to produce harmful molecules, ultimately leading to cellular death.

Other proteins that have similar functions to Parkin can recognize specific amino acid (proteins’ building blocks) sequences on the substances (substrates) in which they act upon. However, Parkin has many substrates that do not appear to have a common amino acid sequence.

To understand Parkin’s selectivity toward a specific sequence, Tokyo Metropolitan Institute of Medical Science investigators investigated whether Parkin could act on mitochondria-targeted artificial proteins (i.e., not found on mammalian cells).

Results revealed that Parkin can act on any protein that contains lysine — an amino acid — but such protein has to be located on the mitochondria’s surface. This means that, unlike its “biological relatives,” Parkin’s activity is not influenced by its substrates’ sequence.

Instead, the control of Parkin activity depends on how this protein is recruited and activated by other proteins.

The team found that Parkin acts more quickly when an ubiquitin molecule is already present, working as a “green-light” for other ubiquitins to be added. Importantly, this first ubiquitin molecule is added by a protein called MITOL, which has never before been associated with Parkinson’s disease.

MITOL is an enzyme present in the membrane of mitochondria that plays a crucial role in the control of this organelle’s morphology.

By targeting MITOL, scientists can potentially increase Parkin’s activity, which may increase efficient mitochondrial repair, and possibly, slow  Parkinson’s progression.

“If we achieve upregulation of ‘seed’ ubiquitylation on mitochondria it might accelerate Parkin recruitment and Parkin activation to eliminate damaged mitochondria more efficiently,” Fumika Koyano, of the Tokyo Metropolitan Institute of Medical Science, said in a press release.

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Next 20 Years Expected to Bring ‘Message of Hope’ to Parkinson’s Patients, Review Study Finds

hope and Parkinson's

Discoveries into molecular mechanisms, risk factors — especially genetic — and advances in potential and repurposed therapies for Parkinson’s disease over the last 20 years are reason to believe that major breakthroughs await the next two decades, a review article by two researchers states.

The review article, “Therapies to Slow, Stop, or Reverse Parkinson’s Disease” was published in a supplement of the Journal of Parkinson’s Disease.

The development of better laboratory models, especially animal models that capture the slowly progressive nature of Parkinson’s, together with data resulting from scientific research and early clinical trials “strongly justifies sending this message of hope,” the authors write, explaining that the mechanisms underlying this neurodegenerative disease are gradually being deciphered.

The researchers, Tom Foltynie at University College London and J. William Langston at Stanford University, highlighted possible therapies that are most likely to emerge as disease-modifying treatments for Parkinson’s, despite the considerable challenges that remain in bringing a treatment successfully through a clinical study.

Based on the knowledge that mutations in the LRRK2 gene are one of the most common genetic causes of Parkinson’s disease, researchers have focused on therapies that can inhibit (block) LRRK2. But these efforts have been hindered by lung complications (lung toxicity) in primates exposed to inhibitor candidates, and scientists are exploring more selective ways of delivering such medications to avoid toxicity.

Questions also remain as to whether the brain is the prime target for LRRK2 activity, with some evidence pointing to the gut as well.

Treatments targeting the GBA gene, which encodes an enzyme called beta-glucocerebrosidase, may be relevant for people with sporadic forms of the disease in whom low levels of beta-glucocerebrosidase have been observed. This enzyme plays an important role in the mobilization and processing of alpha synuclein, which is low in GBA mutation carriers.

Ambroxol, an approved treatment for respiratory diseases associated with sticky or excessive mucus, is known to boost beta-glucocerebrosidase activity. However, it remains to be determined if Parkinson’s patients can tolerate the dose required for this therapy to reach the central nervous system. Other molecules that work in the body in ways similar to Ambroxol have been identified.

Since most available Parkinson’s therapies aim to ease motor symptoms, targeting non-motor features like cognition, speech, gait, balance difficulties and autonomic failure (or problems with regulating blood pressure and other process controlled by the autonomic nervous system) is important, given that many of these may precede motor onset. This could allow treatments to be started earlier, possibly delaying or preventing the onset of motor symptoms.

One approach to slowing disease progression gaining interest is that of “repurposing” medications already approved for diseases other than Parkinson’s. Preclinical studies found that type 2 diabetes medications — scientifically known as glucagon-like peptide 1 (GLP-1) receptor agonists — protect against alpha-synuclein-induced neurodegeneration. Various ongoing Phase 2 trials are assessing the effect of various GLP-1 receptor agonists (liraglutide, lixisenatide and semaglutide ) in Parkinson’s disease patients — NCT03659682NCT03439943NCT02953665). Plans for a Phase 3 trial of exenatide, another GLP-1 agonist, are underway.

Medicines used to treat primary biliary cirrhosis (an autoimmune disease of the liver; ursodeoxycholic acid), chronic myelocytic leukemia (nilotinib) and asthma (salbutamol and clenbuterol) also hold promise for Parkinson’s as they seem to contribute to nerve cell survival, eliminate toxic alpha-synuclein buildup, and modulate alpha-synuclein production, respectively.

Various studies have linked alpha-synuclein-induced neuroinflammation to Parkinson’s disease. As such, immunomodulatory therapies can be a treatment option. Evidence suggests a person’s immune system can react to toxic forms of alpha-synuclein and trigger an inflammatory reaction, which can speed disease progression. Azathioprine and sargramostim, both immunomodulatory medications, are being considered as potential candidates for slowing Parkinson’s progression.

A link between metabolism products generated by gut bacteria and brain inflammation has also been identified, and scientists might look to manipulate the gut microbiome — the trillions of microorganisms and their genetic material that live in the intestinal tract — in Parkinson’s patients, study the effects of such manipulation on the neurodegeneration process.

Lastly, the authors highlighted the possible use of nanoparticles in the disease context, as these molecules have been shown to block the formation of toxic alpha-synuclein clusters and actively work against their aggregation. In theory, nanotechnology might hold the potential to accurately target Parkinson’s-related neuropathology.

“We now have better understanding of the processes involved in PD [Parkinson’s disease] degeneration and can therefore have greater confidence that laboratory data and positive results from early clinical trials will ultimately translate to therapies that slow down PD progression,” Foltynie and Langston said in a news release.

“There are currently no drugs that have been proven to slow down PD progression. Demonstrating that one or several of the candidate approaches is successful will lead to a frameshift in patient care,” they added. “Useful cooperation and coordination between investigators around the globe are significantly accelerating the path towards discovering agents that may slow, stop, or even reverse the progression of PD.”

Their review concluded by stressing the possible importance of combination treatments in future clinical trials.

“It is tempting to speculate that the future patient may be recruited into research reminiscent of the current state of play in HIV/cancer fields, e.g., where following genotyping/ microbiome testing, they are either given the curative enzyme corrective therapy or randomised to receive combination therapies rather than any/each of these alone,” they wrote.

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New Mouse Model Targets Parkinson’s Disease Mechanisms, New Therapies

Parkinson's mouse studies

Researchers have generated a new mouse model that can be used for in-depth studies of disease mechanisms and new therapeutic possibilities for Parkinson’s disease.

Although the function of the protein α-synuclein is unknown, its accumulation in clumps known as Lewy bodies, hallmarks of Parkinson’s disease, suggests this protein plays a role in the pathology of neurodegeneration.

Mutations in GBA1, the gene coding for the enzyme lysosomal glucocerebrosidase 1 (GBA1), have been suggested to play a role in Parkinson’s pathology by enhancing the accumulation of α-synuclein and, consequently, the amount of Lewy bodies. This so-called GBA1-associated Parkinsonism is characterized by an early onset and more severe symptoms of the disease.

The study, “D409H GBA1 mutation accelerates the progression of pathology in A53T α-synuclein transgenic mouse model“, published the journal Acta Neuropathologica Communications, investigated the link between GBA1 mutations and Parkinson’s disease.

By crossing mice that had a GBA1 mutation (known as the D409H mutation) with mice commonly used as models for Parkinson’s disease, researchers created mice with elevated levels of α-synuclein, suggesting that GBA1 plays a role in controlling levels of this protein.

These mice also had a shortened life-span and an earlier onset of neurological disease phenotypes, suggesting that GBA1 plays a role in the pathology of Parkinson’s disease. In fact, in depth-analysis revealed that the GBA1 mutation led to loss of dopaminergic neurons, exacerbated neuroinflammation and endoplasmic reticulum stress, a cellular process that reflects α-synuclein aggregation.

According to researchers these results “indicate that GBA1 deficiency due to D409H GBA1 mutation that contributes to α-synuclein accumulation, exacerbates neuronal vulnerability in neurodegenerative processes.”

This model can be used as a tool to study “the possible mechanisms underlying neurodegeneration due to GBA1 mutations and to test the efficacy of potential treatment against GBA1-associated PD and Dementia with Lewy bodies (DLB),” the researchers stated.

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Source: Parkinson's News Today