The role of mitochondrial genetics in Parkinson's disease: Long-read sequencing as an emerging method

Parkinson's disease (PD) is one of the most devastating neurodegenerative disorders, influenced by a complex interplay of genetic, epigenetic, and environmental factors. Genetic studies and neuropathological evidence suggest that there may be two main forms of early-onset PD driven centrally by either alpha-synuclein aggregation (Lewy bodies) or mitochondrial dysfunction. While numerous studies have utilized omics approaches to investigate the pathogenesis of PD, the role of mitochondrial DNA remains to be fully resolved, in part due to the finite resolution of short-read sequencing technologies. Integrating variations in nuclear and mitochondrial DNA is critical to understanding the etiology of PD and assessing the potential contribution of mitochondrial variation and age-related accumulation of mutations to disease risk. In this review, we explore the role of mitochondrial genetics in PD utilizing long-read sequencing, highlighting its unprecedented versatility in resolving difficult genomic regions and providing critical insights into complex cases of PD.