Mesfer Al Shahrani, United Kingdom
Neurometabolic Unit National Hospital for Neurology and NeurosurgeryAuthor Of 1 Presentation
MITOCHONDRIAL DYSFUNCTION IS A HALLMARK OF THE EARLY PHASE OF SPORADIC PARKINSON’S DISEASE
Abstract
Aims
Capturing the molecular processes that occur in the earliest stages of sporadic Parkinson’s disease (PD) is key to understanding the pathogenesis of disease. Early Braak stage PD brain exhibits a restricted distribution of pathology, and notably the pathological hallmark of neuronal inclusions, exist in a gradient from unaffected-mild-moderate-severe. This spatial pathological gradient provides an opportunity to capture the earliest biochemical changes occurring in the PD brain.
Methods
We combined unbiased large-scale profiling of protein expression using mass spectrometry across 9 Braak brain regions along this gradient (unaffected-severe) to discover common pathways that reflect key processes in early sporadic PD.
Results
Results demonstrate that mitochondrial dysfunction is common to affected PD brain regions. Moreover, alterations in mitochondrial protein expression occur prior to the appearance of significant α-synuclein pathology. Mitochondrial enzyme activity assays support the existence of a gradient of mitochondrial function in PD brain, with a reduction in multiple mitochondrial complexes evident in the severely affected regions, and only a complex 1 deficiency in mildly affected regions.
Conclusions
This study places mitochondrial dysfunction, with α-synuclein aggregation, at the early stages of pathology in the PD brain, rather than as an end stage bystander effect. We further identified key proteins that are altered in regions unaffected by alpha-synuclein pathology, indicating that these markers precede protein aggregation and neuronal death. Our study suggests that mitochondrial function underlies both the cell vulnerability and pathogenic processes in all pathological stages of early PD brain, and is a hallmark of early disease.