November 26, 2025

@michaelokun

Why all the buzz about 'nuclear' alpha synuclein in Parkinson's disease and in other synucleinopathies? Synucleinopathies is a term that refers to neurological disorders where misfolded alpha synuclein disrupts cell function and leads to neurodegeneration. In a new paper in Movement Disorders, Outeiro and Koss describe how nuclear alpha synuclein may be central to genomic instability, DNA damage and the progression of Parkinson's and related synucleinopathies. Key Points: - Nuclear accumulation of alpha synuclein contributes to DNA damage through transcriptional dysregulation, impaired repair pathways and the appearance of double strand and single strand breaks in vulnerable neurons. - Pathological forms of alpha synuclein shift from functional monomers to toxic oligomers w/ increased phosphorylation, which enhances genomic stress, promotes nuclear import disruptions and it seems to seed downstream neurodegenerative cascades. - Cytoplasmic chromatin fragments and mitochondrial DNA leakage interact w/ alpha synuclein, fueling Lewy body formation and amplifying inflammation through pathways such as STING and cGAS. My take: We can't ignore synuclein in Parkinson's and related diseases, however we must look upstream for why the disease starts and understand why it spreads and how it progresses. Here are 5 points that resonated w/ me: 1- Nuclear alpha synuclein matters because it disrupts DNA stability which may in turn accelerate brain cell aging. 2- Toxic forms of the protein frequently impair repair systems, making neurons less capable of recovering from daily cellular stress. 3- Damaged DNA can spill into the cytoplasm, which may trigger the formation of Lewy bodies and raise inflammation. 4- Better detection techniques may allow us to identify 'nuclear' alpha synuclein early, opening new possibilities for prediction of who is at risk and maybe even who will progress faster. 5- New therapies may target nuclear import pathways or DNA repair balance, offering emerging strategies for trying to modify disease progression. https://movementdisorders.onlinelibrary.wiley.com/doi/10.1002/mds.70138 #parkinson #michaelokun #fixelinstitute