Functionality of small protein determined - potential to develop new therapies for Parkinson’s disease

By Samantha Black, Ph.D.

July 28, 2019 -- A small protein, alpha-synuclein, has been found to be associated with the prevention of Parkinson’s disease. Scientists at Oregon Health & Science University (OSHU) published results in the journal Scientific Reports on July 29, 2019 showing that alpha-synuclein has a role in repairing breaks in DNA. The Science Advisory Board recognizes the importance of discoveries like this and is excited to share groundbreaking research with members and the scientific community.

According to Parkinson’s Foundation, Parkinson’s disease is the 14th leading cause of death in the United States and over 10 million people worldwide live with Parkinson’s disease.

Alpha-synuclein is a presynaptic protein that forms Lewy bodies. Lewy bodies are abnormal aggregates of alpha-synuclein that develop inside nerve cells. They displace other cell components. Parkinson’s disease is associated with the accumulation of Lewy bodies found in substantia nigra neurons (where dopamine neurons originate in the midbrain) which impair neurons and prevent the production of dopamine.

Researchers have determined alpha-synuclein localization, however its function in the nucleus is not well understood. OHSU scientists demonstrate that alpha-synuclein modulates DNA repair.

Problematic Lewy bodies pull alpha-synuclein out of the nucleus of brain cells, which leads to increased neuron death and development of Parkinson’s disease and other neurodegenerative disorders. The current study suggests that alpha-synuclein plays a crucial role in repairing breaks that occur in DNA present in the nucleus of cells called DNA double-strand breaks (DSBs).

Researchers found that the alpha-synuclein protein rapidly recruited to the site of DNA damage in the neurons of mice. In addition, they found increased DSBs of human tissue and mice in which the protein was clumped together in the form of Lewy bodies in the cytoplasm surrounding the cell's nucleus. A combination of approaches in HAP1 cells, including immunocytochemistry (ICC), nuclear fractionation, western blotting and the neutral comet assay on wild-type and alpha-synuclein gene (SNCA) knock-out cells, provided direct evidence that alpha-synuclein plays a role in regulating cellular repair responses to induced DSBs. To describe is more simply: alpha-synuclein is important in binding broken DNA strands within the nucleus of cells.

Immunocytochemistry: a common laboratory technique used to visualize an antigen (protein) in cells by use of specific primary antibody that binds to it. Visualization occurs under a florescence microscope when the primary antibody is bound by a secondary antibody which forms a fluorophore. This technique allows researchers to determine which sub-cellular components are expressing the antigen in question.
Neutral comet assay: a sensitive technique used for the detection of DNA damage in eukaryotic cells, otherwise known as single cell gel electrophoresis. The technique is based on micro-electrophoresis of cells DNA content. Damaged DNA migrates forming a tail of a “comet” while in-tact DNA will remain in the head of the “comet”. The assay can be applied to different cell types.

So, what is the significance of this discovery in terms of therapies for individuals with Parkinson’s disease? Researchers hope to develop methods to deliver alpha-synuclein proteins into the nucleus of cells or design other molecules that can replicate its functions within neurons.



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