Critical Role of Truncated α-Synuclein and Aggregates in Parkinson's Disease and Incidental Lewy Body Disease

• Published in: Brain pathology (Zurich, Switzerland) Vol. 22; no. 6; pp. 811 - 825
• Main Authors: Prasad, Kavita, Beach, Thomas G., Hedreen, John, Richfield, Eric K.
• Format: Journal Article
• Language: English
• Published: Oxford, UK Blackwell Publishing Ltd 01-11-2012
• Subjects: Aged; alpha-Synuclein - metabolism; Autopsy; Brain - metabolism; Brain - pathology; Female; Humans; Immunohistochemistry; Incidental Findings; Indexing in process; Lewy Body Disease - complications; Lewy Body Disease - metabolism; Lewy Body Disease - pathology; Male; Microscopy, Confocal; nucleus basalis of Meynert; Parkinson Disease - complications; Parkinson Disease - metabolism; Parkinson Disease - pathology; Parkinson's disease; putamen; substantia nigra; α-synuclein
• ISSN: 1015-6305; 1750-3639
• DOI: 10.1111/j.1750-3639.2012.00597.x

The role of Lewy bodies, Lewy neurites and α‐synuclein (αSYN) in the pathophysiology and diagnosis of Parkinson's disease (PD) is unclear. We used postmortem human tissue, a panel of antibodies (Abs) and confocal microscopy to examine the three‐dimensional neurochemical anatomy of the nigrostriatal system. Abs were specific to truncated (tαSYN), phosphorylated and full‐length αSYN. The findings demonstrate the critical role of tαSYN in initiating aggregation, a role for other forms of αSYN in aggregate expansion, a reason for the wide variety of proteins present in different aggregates, an explanation for the laminar appearance of aggregates described historically using different methods, the existence of proximal greater than distal aggregation in the vulnerable nigrostriatal pathway, the independent transport of different forms of αSYN as cargo along axons and a possible sequence for the formation of Lewy bodies. Findings differed between incidental Lewy body disease and PD only quantitatively. These findings have implications for understanding the pathogenesis and treatment of PD.