α-synuclein phosphorylation and truncation are normal events in the adult human brain

α-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 α-synuclein have been associated with selective neuronal vulnerability to Lewy pathology. Furthermore, phosphorylation at serine 129 (Ser129) and α-synuclein truncation have been considered crucial in the pathogenesis of Lewy inclusions. The present study shows consistent reduction in α-synuclein protein expression levels in the human substantia nigra and nucleus basalis of Meynert compared with other brain regions independently of age and pathology. Phosphorylated α-synuclein at Ser129 is naturally increased in these same regions, thus inversely related with the total amount of α-synuclein. In contrast, truncated α-synuclein is naturally observed in control and diseased brains and correlating with the total amount of α-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 α-synuclein variants and phosphorylated α-synuclein occurs in Lewy bodies, α-synuclein phosphorylation and truncation can be considered constitutive in control and diseased brains.

▶αsynuclein protein levels are lower in the human substantia nigra and nucleus basalis of Meynert compared with other brain regions. ▶The reduction in α-synuclein protein levels in these two human brain regions is independent of age and pathology. ▶Phosphorylated α-synuclein is increased in substantia nigra and nucleus basalis of Meynert, inversely correlating with the total amount of α-synuclein. ▶Truncated α-synuclein is a general event present in normal and Lewy body disease brains and is not related to pathology or age.