Topographical Propagation of alpha-synuclein Pathology in Parkinson's Disease: Phenomenology and Hypothetical Mechanism

ABSTRACT

Parkinson's disease is an age-related, slowly progressing neurodegenerative disorder characterized by abnormal deposition of aggregated alpha-synuclein in neuronal cell bodies (Lewy bodies) and neurites (Lewy neurites), as well as in glia. Based on semiquantitative assessment of Lewy pathologies in autopsy samples, a staging system was proposed indicating a highly predictable sequence of pathological progression. This staging system implicates a propagation of alpha-synuclein aggregation throughout the brain with an ascending pattern from lower brain stem to neocortex. The underlying mechanism for the pathological propagation is unknown. However, the recent discoveries on the secretion of neuronal alpha-synuclein and subsequent uptake of the protein by neighboring cells propose an interneuronal transmission of alpha-synuclein aggregates as a novel mechanism for the spread of Lewy pathology in PD. Elucidation of this mechanism is likely to identify novel therapeutic strategies that halt the progression of PD.