December 14, 2025

@michaelokun

Looking for a good review on alpha synuclein and Parkinson’s disease? Alpha synuclein is a nerve cell protein that normally helps package and move chemical messengers. In PD it can misfold, clump and potentially spread injury from synapse to synapse. Calabresi and colleagues describe in Cell Death and Disease how alpha synuclein shifts from helper protein to potential troublemaker and may drive early synaptic dysfunction, inflammation and ultimately cell loss in PD and related synucleinopathies. Key Points: - Alpha synuclein starts trouble at the synapse long before cells die by mechanisms: disrupting dopamine release, calcium balance and vesicle recycling especially in highly active neurons. - Different brain cells and circuits are not equally vulnerable since long, energy hungry dopamine neurons in substantia nigra hit hardest by toxic alpha synuclein aggregates and mitochondrial stress. - Alpha synuclein misfolding may fuel inflammation as microglia, astrocytes and immune cells react to the aggregates, which may accelerate spread across the brain and shape different synuclein disorders like PD, DLB and MSA. My take: It will be important for us to understand ‘normal and abnormal synuclein’ as we proceed on our journey to understand PD. There were 5 points that resonated w/ me from this fantastic review article: 1- Think early synapse changes not just late nerve cell death, because synuclein can quietly damage communication in brain circuits years before classic motor signs of PD appear. 2- Watch the whole synuclein family since a similar alpha synuclein problem shows up in PD, dementia w/ Lewy bodies, multiple system atrophy and pure autonomic failure. 3- Biomarkers for alpha synuclein in CSF, blood, skin and other tissues +new seeding assays together aim to catch toxic forms early. 4- Therapies are moving beyond dopamine replacement toward alpha synuclein targeting strategies such as vaccines, antibodies and aggregation blockers that try to slow disease rather than simply mask symptoms. 5- The future likely needs a combo approach that will tackle alpha synuclein, inflammation, mitochondrial stress and genetics; and of course environment. #michaelokun