How α-Synuclein Aggregration Kills Neurons in Parkinson’s Disease

Parkinson’s disease is strongly linked to quality control of mitochondria in neurons. The condition is characterized by the loss of a vital population neurons responsible for generating the neurotransmitter dopamine, and it is this loss that produces the tremors and other motor dysfunction observed in patients. Parkinson’s disease is also a proteopathy, however, in which α-synuclein clumps together to form solid deposits that harm brain cells. In the research noted here, scientists show that this α-synuclein aggregation kills neurons by damaging mitochondria and triggering mitochondrial mechanisms that produce the form of cell death called apoptosis. This might suggest a link to what is already known of the important portions of the biochemistry of Parkinson’s disease; more active mitochondrial quality control might slow the harm done by α-synuclein by removing damaged mitochondria before they can trigger apoptosis.

Parkinson’s disease isn’t the only synucleinopathy in which α-synuclein aggregation harms the function of the brain. Synucleinopathies are not the only class of proteopathy in the brain: amyloids and tau also form aggregates that are involved in the development of neurodegenerative conditions such as Alzheimer’s disease. Finding ways to safely and reliably remove the excess molecular waste that accumulates within and between brain cells is a very important topic in medical research. Controlling one form of waste should provide benefits to patients suffering any of several varieties of neurodegeneration, but since aging brains tend to exhibit the signs of all of these forms of protein aggregate, clearing out all of them is most likely necessary in order to prevent or cure the most common age-related neurodegenerative conditions.

For years, scientists have known that Parkinson’s disease is associated with a build-up of alpha-synuclein protein inside brain cells. But how these protein clumps cause neurons to die was a mystery. Using a combination of detailed cellular and molecular approaches to compare healthy and clumped forms of alpha-synuclein, researchers have discovered how the protein clumps are toxic to neurons. They found that clumps of alpha-synuclein moved to and damaged key proteins on the surface of mitochondria – the energy powerhouses of cells – making them less efficient at producing energy. It also triggered a channel on the surface of mitochondria to open, causing them to swell and burst, leaking out chemicals that tell the cell to die.

These findings were replicated in human brain cells, generated from skin cells of patients with a mutation in the alpha-synuclein gene, which causes early-onset Parkinson’s disease. By turning patient skin cells into stem cells, they could chemically guide them into become brain cells that could be studied in the lab. This cutting-edge technique provides a valuable insight into the earliest stages of neurodegeneration – something that brain scans and post-mortem analysis cannot capture. “Our findings give us huge insight into why protein clumping is so damaging in Parkinson’s, and highlight the need to develop therapies against the toxic form of alpha-synuclein, not the healthy non-clumped form.”

Link: https://www.crick.ac.uk/news/science-news/2018/06/12/scientists-unravel-molecular-mechanisms-of-parkinson%E2%80%99s-disease/

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