4.7 Article

Early Forms of α-Synuclein Pathology Are Associated with Neuronal Complex I Deficiency in the Substantia Nigra of Individuals with Parkinson's Disease

期刊

BIOMOLECULES
卷 12, 期 6, 页码 -

出版社

MDPI
DOI: 10.3390/biom12060747

关键词

OXPHOS; mitochondria; synucleinopathy; alpha-synuclein; Lewy-pathology; respiratory chain

资金

  1. Research Council of Norway [288164]
  2. Bergen Research Foundation [BFS2017REK05]
  3. Western Norway Regional Health Authority [F-10229-D11661]

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Early alpha-synuclein aggregation is associated with mitochondrial respiratory complex I (CI) deficiency in neurons of idiopathic Parkinson's disease (iPD), and there is selective loss of neurons affected by both pathologies.
Idiopathic Parkinson's disease (iPD) is characterized by degeneration of the dopaminergic substantia nigra pars compacta (SNc), typically in the presence of Lewy pathology (LP) and mitochondrial respiratory complex I (CI) deficiency. LP is driven by alpha-synuclein aggregation, morphologically evolving from early punctate inclusions to Lewy bodies (LBs). The relationship between alpha-synuclein aggregation and CI deficiency in iPD is poorly understood. While studies in models suggest they are causally linked, observations in human SNc show that LBs preferentially occur in CI intact neurons. Since LBs are end-results of alpha-synuclein aggregation, we hypothesized that the relationship between LP and CI deficiency may be better reflected in neurons with early-stage alpha-synuclein pathology. Using quadruple immunofluorescence in SNc tissue from eight iPD subjects, we assessed the relationship between neuronal CI or CIV deficiency and early or late forms of LP. In agreement with previous findings, we did not observe CI-negative neurons with late LP. In contrast, early LP showed a significant predilection for CI-negative neurons (p = 6.3 x 10(-5)). CIV deficiency was not associated with LP. Our findings indicate that early alpha-syn aggregation is associated with CI deficiency in iPD, and suggest a double-hit mechanism, where neurons exhibiting both these pathologies are selectively lost.

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