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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Man-made DNA Molecules May Help Prevent Parkinson’s, Study Finds

man made DNA molecules

Osaka University scientists have built short fragments of DNA that can stop the production of abnormal alpha-synuclein protein in the brain — which may advance the development of new therapies for the control and prevention of Parkinson’s disease.

The study, “Amido-bridged nucleic acid (AmNA)-modified antisense oligonucleotides targeting α-synuclein as a novel therapy for Parkinson’s disease,” was published in Scientific Reports.

“Although there are drugs that treat the symptoms associated with PD [Parkinson’s disease], there is no fundamental treatment to control the onset and progression of the disease,” Takuya Uehara, PhD, the study’s lead author, said in a press release.

It is believed that gene therapy could someday be used to treat or halt Parkinson’s. Potential therapeutic targets include genes associated with the disorder, such as the SNCA gene — the gene that codes for the alpha-synuclein protein. Mutations in SNCA lead to the production and accumulation of an abnormal, and harmful, form of the alpha-synuclein protein within brain cells of people with Parkinson’s. As the disease progresses, neuronal toxic protein buildup increases, eventually leading to cellular death. That, in turn, leads to the onset of disease-related motor and non-motor symptoms.

“The antisense oligonucleotide (ASO) is a potential gene therapy for targeting the SNCA gene. ASO-based therapies have already been approved for neuromuscular diseases including spinal muscular atrophy (SMA) [Spinraza] and Duchenne muscular dystrophy [Exondys 51],” the researchers said.

Japanese researchers now looked for ways to prevent the production of toxic alpha-synuclein, hoping to eliminate Parkinson’s molecular trigger. To do so, they designed 50 small fragments of DNA that mirrored parts of  the coding sequence of the SNCA gene messenger RNA (mRNA).

All genetic information contained within genes (DNA) is ultimately translated into proteins. However, several complex steps exist before a protein can be produced: DNA is first transformed into mRNA, and eventually, into a protein.

The man-made DNA fragments, also known as amido-bridged nucleic acid-modified antisense oligonucleotides (AmNA-ASO), were stabilized with resilient cyclic amide structures (hence the term “amido-bridged”). Amide are compounds that confer structural rigidity.

In total, these 50 molecules covered around 80.7% of SNCA’s mRNA. In doing so, engineered molecules were able to bind to their matching natural mRNA sequence, disabling it from being translated into a protein.

Using human embryonic kidney cells that naturally produce alpha-synuclein, scientists observed that several of these engineered molecules reduced SNCA mRNA levels. One of the constructs, specifically number 19, significantly decreased SNCA mRNA levels to 24.5% of the normal alpha-synuclein levels, “suggesting that AmNA-ASO [number] 19 is highly potent for targeting SNCA mRNA in human cultured cells,” the researchers said.

Importantly, this particular ASO was efficiently delivered into the brains of mice using an intracerebroventricular (a fluid-filled interconnected brain cavity) injection, without the aid of additional chemical carriers. The ASO was then mainly taken up by neurons and neuronal support cells.

Further testing, using a Parkinson’s mouse model that had disease-characteristic motor impairment, revealed AmNA-ASO number 19 successfully reduced alpha-synuclein protein levels, and significantly eased symptom severity 27 days after administration.

The researchers concluded that reducing alpha-synuclein mRNA and corresponding protein levels via gene therapy seems to enhance Parkinson’s-related motor manifestations in mice. This highlighted AmNA-ASO’s potential as a novel therapy for this neurodegenerative disorder.

The ASO Spinraza (nusinersen) was approved by the U.S. Food and Drug Administration (FDA) in December 2016 for treating spinal muscular atrophy. The FDA granted accelerated approval to Exondys 51 (eteplirsen) in September 2016, making it the first drug approved to treat Duchenne muscular dystrophy.

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DNA Mutations Acquired Before Birth May Lead to Parkison’s in Adulthood, Study Suggests

DNA mutations and brain development

Spontaneous mutations that occur in DNA before birth — part of cell division and reproduction in the growing brain — can predispose a person to neurodegenerative diseases in adulthood and may be more common than thought, a research team led by the University of Cambridge suggests.

Its findings may explain the onset of such disorders in people without a family history of diseases like Alzheimer’s and Parkinson’s.

The study, “High prevalence of focal and multi-focal somatic genetic variants in the human brain,” was published in Nature Communications.

The causes of neurodegenerative diseases are essentially unknown. Most are sporadic — meaning they simply appear in a person —  although hereditary cases are known and well-documented.

Clinical presentation of hereditary forms is frequently like the sporadic types, suggesting that common biological processes underlie both forms of neurodegenerative diseases.

“As the global population ages, we’re seeing increasing numbers of people affected by diseases such as Alzheimer’s, yet we still don’t understand enough about the majority of these cases,” Patrick Chinnery, the study’s lead author, said in a press release.

“Why do some people get these diseases while others don’t? We know genetics plays a part, but why do people with no family history develop the disease?” added Chinnery, who is also with the Medical Research Council (MRC) Mitochondrial Biology Unit and a professor in the Department of Clinical Neurosciences at Cambridge.

Chinnery’s team hypothesized that spontaneous mutations within specific clusters of brain cells could contribute to the misfolded protein synthesis found in neurodegenerative diseases, and that such molecular phenomenon could have the potential to spread throughout the brain as a person aged.

Investigators used frozen brains acquired from the Newcastle Brain Tissue Resource, part of MRC’s U.K. Brain Banks Network. Among the 54 brains examined, 20 were from people with Alzheimer’s, 20 with those Lewy body dementia, and 14 who had no family history of any neurodegenerative disorder and showed features consistent with normal aging (samples in this group were from healthy people age 65 and older).

A total of 173 brain tissue samples were examined.

Using a novel sequencing technique, the researchers sequenced — more than 5,000 times — 102 genes known to cause or put a person at risk of a neurodegenerative disease. Around 611,285 cells were sequenced.

The team reported 39 somatic mutations in 27 of the 54 examined brains, including both healthy (control) and diseased samples.

Somatic mutations are spontaneous genetic mutations (i.e., errors in DNA) acquired by a cell and occurring after conception. As cell division progresses during embryonic development, mutated cells will continue to be produced until the body that harbors those cells dies. But these somatic mutations cannot be passed to offspring because they do not occur in germ cell DNA, which are the cells that create sperm or egg.

Eighteen spontaneous mutations (56.4% of the total 39 detected “genetic errors”) were present in only one brain region — although in many cells there, while 17 others (43.6% of 39 mutations) occurred in more than one brain region.

Because the single region mutations occurred in numerous cells, it is highly probable that such DNA errors happened during embryo development, the scientists said.

Researchers then used a simplified mathematical model of neurodevelopment to help them understand their data. They inferred a mutation rate, simulated brain development using their model, and found that each individual tended to have 100,000 to 1 million disease-related mutated cells, suggesting that these mutations occur often in the general population.

Frame-shift mutations, i.e., an insertion or deletion of genetic material into the DNA sequence, in cell proliferation and differentiation disorder genes were detected in 40% of samples taken from people with Lewy body dementia, in comparison to 7% in those from the control group.

“These spelling errors arise in our DNA as cells divide, and could explain why so many people develop diseases such as dementia when the individual has no family history,” Chinnery said. “These mutations likely form when our brain develops before birth — in other words, they are sat there waiting to cause problems when we are older.

“Our discovery may also explain why no two cases of Alzheimer’s or Parkinson’s are the same,” he added. “Errors in the DNA in different patterns of brain cells may manifest as subtly different symptoms.”

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