Variable expression of mitochondrial complex IV in the course of nigral intracellular accumulation of α-synuclein

Abstract

Introduction: Parkinson's disease (PD) is a neurodegenerative disease characterized by the deposition of disease-associated α-synuclein, which is thought to follow a sequential distribution in the human brain. Accordingly, α-Synuclein pathology affects the substantia nigra (SN) only in Braak stage 3 out of 6. Moreover, intracellular accumulation of α-synuclein follows maturation from non-ubiquitinated (p62 negative) to ubiquitinated (p62 positive) forms (Lewy bodies). Mitochondrial dysfunction is thought to be a central player in the pathogenesis of PD. It is not clear whether the nigral neurons already show mitochondrial alterations in stages preceding the deposition of α-synuclein in the SN, and how deposition of pre-aggregates or ubiquitinated mature inclusions relate to this.

Methods: Using cell-based morphometric immunohistochemistry we evaluated the volume density of mitochondrial complex-IV (COX-IV) immunoreactivity in SN neurons lacking or showing α-synuclein deposits in non-diseased individuals and those with Lewy body pathology Braak stage <3 lacking nigral α-synuclein pathology and Braak stage >3 with prominent nigral α-synuclein deposition.

Results: Increased volume density of COX-IV immunoreactivity appears before detectable pathological α-synuclein in nigral neurons. The volume density decreases significantly as pathological pre-aggregates of α-synuclein accumulates in the neurons and remains at a low level in neurons with p62 positive Lewy bodies.

Conclusions: COX-IV expression shows a change before and during accumulation of α-synuclein in the SN underpinning the role of early mitochondrio protective therapy strategies in PD.

Keywords: COX-IV; Mitochondria; Oligomer; Parkinson's disease; p62; α-synuclein.