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Brain Development Discovery Could Have Implications for Parkinson’s, Other Neurological Diseases

brain development

An inflammatory pathway that plays a key role in the proper removal of faulty cells during brain development could open new avenues for studying or treating neurological diseases, including Parkinson’s.

The study, “AIM2 inflammasome surveillance of DNA damage shapes neurodevelopment,” was published in Nature.

During normal development, cells in the brain grow rapidly; then about half of these newly-made cells are “pruned back,” dying off in tightly regulated ways. Abnormalities in this process are believed to underlie a wide range of neurological conditions, but the exact mechanisms that control this development are still not fully understood.

Inflammasomes are groups of proteins that act together to drive inflammation in response to certain molecular triggers. For example, the AIM2 inflammasome is activated by damaged or irregular DNA, which can accumulate in cells that are infected with viruses or bacteria. In the new study, researchers demonstrated that the AIM2 inflammasome also plays an important role in brain development.

The team, led by University of Virginia (UVA) researchers, first observed evidence of inflammasome activation in the developing brain in mice. Then they genetically engineered mice that lacked genes critical for inflammasome formation. These mice had abnormal anxiety-like behaviors, suggestive of brain abnormalities.

Because damaged DNA is a known activator of the AIM2 inflammasome, the researchers sought to understand whether the DNA damage that normally occurs during neurodevelopment (as a consequence of rapid cellular division, for example) could trigger activation of the AIM2 inflammasome in the developing brain.

“You don’t want [brain] cells to have genomic compromises. You don’t want damaged DNA. So, this would be a normal mechanism to expel those cells from being incorporated into the central nervous system,” study co-author Catherine R. Lammert, a graduate student at UVA, said in a press release.

The results revealed that within mice’s brain cells, inflammasomes were located close to areas of DNA damage, and when extra DNA damage was induced (with radiation), inflammasome activation increased.

This model effectively suggests that the inflammasome could serve as a sort of “clean-up” for damaged cells.

Furthermore, in mice lacking functional inflammasomes, there was less cell death during brain development, but also more DNA damage in the developed brain. And, when DNA damage was induced in these mice with radiation, there was less resultant cell death than when the same treatment was given to wild-type mice with functional inflammasomes.

Collectively, these data support a model where AIM2 inflammasome activation is necessary for the cell death that is part of normal brain development — specifically, that the inflammasome helps to remove cells with damaged DNA.

The exact manner of inflammasome-induced cell death was noteworthy, because it previously was believed that, in the developing brain, cell death occurs via apoptosis (a type of programmed, non-inflammatory cell death). However, this idea is based on an outdated framework wherein apoptosis was the only form of programmed cell death, which is an orchestrated series of steps the cell undertakes as it dies. The alternative would be necrosis, in which a cell is simply destroyed.

However, other forms of programmed cell death have been discovered recently. The researchers found evidence that the AIM2 inflammasome participates in one of these, called pyroptosis, a programmed form of inflammatory cell death that is mediated by the protein gasdermin-D.

“Neurodevelopment is a very complicated process. This form of cell death actually plays a role in removing unwanted cells from the brain to establish a healthy [central nervous system] with the correct connections and the right number of cells,” Lammert said.

Because abnormal brain development underlies so many neurological conditions, better comprehension of how these systems work could aid in understanding those conditions, or even developing new therapeutic strategies.

“Hitting this pathway in the mature brain would likely provide a treatment strategy for any neurodegenerative disease associated with DNA damage, and that’s all the major heavy hitters: Alzheimer’s disease, Parkinson’s, [amyotrophic lateral sclerosis] ALS,” said study co-author John Lukens, PhD, a UVA professor.

The post Brain Development Discovery Could Have Implications for Parkinson’s, Other Neurological Diseases appeared first on Parkinson’s News Today.

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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Perillyl Alcohol Lowers Toxicity, Cell Death in Parkinson’s Cell Model, Study Reports

perillyl alcohol, Parkinson's study

A plant-derived compound called perillyl alcohol restored cell survival and lowered oxidative stress and DNA damage in a cell model of Parkinson’s disease, according to researchers.

The new study, “Evaluation of phytomedicinal potential of perillyl alcohol in an in vitro Parkinson’s Disease model,“ was published in the journal Drug Development Research.

For cells to create energy, they “breathe” oxygen received by the food we eat and the air we breathe, and as a result, reactive molecules are created. These residual molecules are the free radicals responsible for oxidative stress.

In addition, in our everyday life, our bodies are exposed to reactive oxygen species (ROS) as a result of the environment around us. When something doesn’t work well in the energy extraction process and cells become full of ROS compounds, oxidative stress occurs.

Oxidative stress and dysfunction in mitochondria (the cells’ powerhouses that produce energy) are implicated in Parkinson’s development.

In laboratory animal models, neurotoxin 6-hydroxydopamine (6-OHDA) — which causes oxidative stress and impairs the cellular production of energy — is one of the most frequently used neurotoxins to induce Parkinson’s disease by generating ROS.

Preclinical studies of other neurodegenerative disorders, such as Alzheimer’s and Huntington’s diseases, have reported that using antioxidants can ease cell toxicity.

Perillyl alcohol (PA), commonly found in peppermint, lemongrass, lavender, and sage, has shown anti-cancer activity in animal models and human patients.

Besides being a natural compound, its inexpensive production and lack of adverse events with intranasal (through the nose) delivery make PA a potential Parkinson’s therapy. However, no studies have evaluated this compound in a Parkinson’s model.

Researchers at Aligarh Muslim University in India assessed the ability of perillyl alcohol to lower ROS generation, mitochondrial dysfunction, and resulting cell toxicity in a cell line (SH-SY5Y) treated with 6-OHDA (150 μM).

SH-SY5Y is a human origin neuroblastoma (a type of brain tumor) cell line that is capable of emulating physiological conditions of neurons and as such, has been used to model various neuronal disorders in the laboratory, including Parkinson’s.

Pretreatment (one hour before 6-OHDA administration) with both 10 and 20 μM concentrations of PA significantly improved cells’ viability, which usually falls below 50% due to the effects of the neurotoxin. Importantly, PA had no toxic effects on these cells and lowered 6-OHDA-induced ROS generation in a dose-dependent manner.

Perillyl alcohol was able to partially restore the decreased mitochondrial membrane potential (MMP) — an indicator of its functional status and associated with cell survival — caused by 6-OHDA.

PA also decreased cell death, as observed by decreased mitochondrial release of cytochrome c, which is often released from mitochondria during the early stages of apoptosis (“programmed” cell death).

Protection from DNA damage (or fragmentation), which plays a key role in the development of neurodegenerative diseases, was also achieved with both doses of perillyl alcohol.

“We have come to the conclusion that PA demonstrates sufficient neuroprotective activity to provide new avenues in therapy of [Parkinson’s] and its apparent target being restoration of MMP can lead to better understanding of the disease,” the researchers wrote.

However, they cautioned that in vivo (animal) studies are required to fully characterize perillyl alcohol’s effectiveness and mechanism of action.

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Source: Parkinson's News Today

Mitochondria Defects in Brains of Parkinson’s Patients Might Play Protective Role

mitochondria complex-I

Defects in mitochondria, the cell’s microscopic powerhouses, might actually protect Parkinson’s disease patients, a Norwegian study suggests.

The findings show that, contrary to all current theories, deficiencies in complex I — a key component of mitochondria — exist randomly throughout the brains of Parkinson’s patients, not only in affected regions. In addition, researchers think these deficiencies protect against the formation of protein aggregates.

Their study, “Neuronal complex I deficiency occurs throughout the Parkinson’s disease brain, but is not associated with neurodegeneration or mitochondrial DNA damage,” appeared in Acta Neuropathologica.

Mitochondria are tiny structures within cells that produce all the energy needed for survival. The process of energy production relies on several protein complexes.

In 1989, researchers found that one of these complexes, complex I, was impaired in neurons from the substantia nigra of Parkinson’s patients. This brain region is particularly vulnerable to Parkinson’s disease, which led to the hypothesis that complex I deficiencies were caused by accumulating mitochondrial DNA damage in these neurons and contribute to neurodegeneration.

But a new study by Norway’s University of Bergen contradicts this decades-old hypothesis.

“We hypothesized that if complex I deficiency is actively involved in the neurodegenerative process of PD, it should not be limited to the [substantia nigra], but extend to other regions of the brain involved in the disease,” they said.

To address this question, they examined the activity and function of complex I in different brain regions of Parkinson’s patients, and compared them with those of healthy volunteers.

Interestingly, they found complex I deficiency not only in substantia nigra, but throughout the brains of Parkinson’s patients — including areas not affected by the neurodegenerative process, like the cerebellum.

With the exception of cells in the substantia nigra, no correlation existed between complex I loss and mitochondrial DNA damage load.

“This new study shows that complex-I deficiency is, in fact, a global phenomenon in the brains of persons with Parkinson’s disease, and is found indiscriminately in both affected and healthy brain regions,” Charalampos Tzoulis, principal investigator at the University of Bergen’s Department of Clinical Science and senior author of the study, said in a news release.

The team found that neurons lacking complex I function were significantly less likely to develop Lewy bodies, the aggregates of protein fibrils that are a hallmark of Parkinson’s disease.

“It is possible that complex-I deficiency is part of a compensatory regulation attempting to protect the brain in Parkinson’s disease, for instance via decreased production of oxidative free radical species,” Tsouliz said. “Irrespective of whether it is a pathogenic event or compensatory response, the extent of neuronal complex-I deficiency in [Parkinson’s disease] suggests that it is an important and inherent part of the disorder.”

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Source: Parkinson's News Today