α-SYNUCLEIN PHOSPHORYLATION AND TRUNCATION ARE NORMAL EVENTS IN THE ADULT HUMAN BRAIN

alpha-synuclein is a key protein in Lewy body diseases (LBDs) and a major component of Lewy bodies and related aberrant cytoplasmic and neuritic inclusions. Regional differences in alpha-synuclein have been associated with selective neuronal vulnerability to Lewy pathology. Furthermore, phosphorylation at serine 129 (Ser129) and alpha-synuclein truncation have been considered crucial in the pathogenesis of Lewy inclusions. The present study shows consistent reduction in a-synuclein protein expression levels in the human substantia and nucleus basalis of Meynert compared with other brain regions independently of age and pathology. Phosphorylated alpha-synuclein at Ser129 is naturally increased in these same regions, thus inversely related with the total amount of alpha-synuclein. In contrast, truncated alpha-synuclein is naturally observed in control and diseased brains and correlating with the total amount of alpha-synuclein. Several truncated variants have been identified where some of these variants are truncated at the C-terminal domain, whereas others are truncated at the N-terminal domain, and all are present in cases with and without Lewy pathology. Although accumulation of truncated alpha-synuclein variants and phosphorylated alpha-synuclein occurs in Lewy bodies, alpha-synuclein phosphorylation and truncation can be considered constitutive in control and diseased brains. (C) 2011 IBRO. Published by Elsevier Ltd. All rights reserved.