Point mutations in the α-synuclein gene (SNCA), as well as duplication or triplication of wild-type SNCA, cause autosomal-dominant Parkinson’s disease. α-synuclein is abundantly expressed in the nervous system. In neurons, the protein is primarily localized to presynaptic terminals.
Under normal conditions, α-synuclein exists as a natively unfolded monomer or is bound to membranes with an a-helical secondary structure. Though the protein’s primary physiological function remains ambiguous, it has been implicated in synaptic vesicle trafficking, neurotransmitter release, and fatty acid uptake.
α-synuclein is a major component of Lewy bodies and Lewy neurites, intracellular aggregates that represent a neuropathologic hallmark of synucleinopathies such as Parkinson’s disease (PD), Dementia with Lewy bodies (DLB), and Multiple system atrophy (MSA). Lewy bodies are also found in many patients with Alzheimer’s disease.
Early in the path to forming these fibrillar, insoluble aggregates, the α-synuclein protein accumulates, misfolds, and aggregates into soluble oligomeric species. α-synuclein can be secreted and taken up by other cells; it is thought that misfolded α-synuclein propagates from one cell to anatomically connected cells, triggering aggregation in the recipient cell. In this way, a slow spread from the brainstem to limbic and neocortical areas would give rise to the stereotypical pattern of Lewy body pathology in PD.
These smaller aggregates may be the main pathogenic species that cause degeneration of dopaminergic neurons. α-synuclein-induced neurotoxicity may involve remodeling of membranes, impairment of mitochondria, and dysfunction of the autophagy-lysosomal pathway.
High levels are associated with impaired cognition in humans and in transgenic mouse models, and soluble α-synuclein is elevated in AD brain. The concentration of α-synuclein in the CSF is reduced in PD and DLB, and it is being explored as a potential biomarker for the differential diagnosis of these diseases against AD. Co-occurring α-synuclein and Aβ or tau pathology is a sign of worse prognosis and frequently marks mixed disease such as DLB or Parkinson’s disease dementia (PDD.) PET tracers for α-synuclein are at the animal research stage. α-synuclein is a drug target, and therapeutic antibodies are beginning to enter early stage clinical trials.
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