A 140-amino-acid presynaptic protein whose misfolding and aggregation into Lewy bodies is the pathological hallmark of parkinsons disease and other synucleinopathies. The "gut-first" hypothesis proposes that alpha-synuclein pathology originates in the enteric nervous system and propagates to the brain via the vagus nerve.
Metal Interactions
- iron: Fe(III) directly accelerates alpha-synuclein fibrillization; iron accumulates in the substantia nigra of PD patients. ferroptosis (iron-dependent cell death) is implicated in dopaminergic neuron loss.
- copper: Cu(II) binds alpha-synuclein at the N-terminus and promotes oligomerization. Copper dyshomeostasis is documented in PD brain tissue.
- manganese: Chronic manganese exposure causes manganism (parkinsonism); Mn promotes alpha-synuclein aggregation and mitochondrial dysfunction.
- lead: Developmental lead exposure upregulates alpha-synuclein expression decades later (epigenetic programming).
Gut-Brain Connection
- Alpha-synuclein is expressed in enteric neurons; dysbiosis and inflammation in the gut may trigger its misfolding.
- Gut microbiome composition (specifically short chain fatty acids producers) modulates alpha-synuclein aggregation in animal models.
- The gut brain axis provides the anatomical route for prion-like spread from gut to brain.
Connections
- parkinsons disease — alpha-synuclein aggregation is the defining pathology
- ferroptosis — iron-dependent cell death pathway in dopaminergic neurons
- neuroinflammation — microglial activation by aggregated alpha-synuclein
- gut brain axis — vagal transmission of pathological alpha-synuclein
- oxidative stress — metal-catalyzed ROS generation promotes misfolding