Mitochondrial Neurodegenerative Disorders I: Parkinsonism and Cognitive Deficits

Abstract

Parkinson’s disease is the second most common neurodegenerative disease, and the distinctive neuropathological hallmarks are the progressive death of dopaminergic substantia nigra neurons and the intracellular accumulation of alpha-synuclein into Lewy bodies. There are emerging lines of evidence to suggest that mitochondrial dysfunction is central to the final metabolic failure of dopaminergic neurons in Parkinson’s disease. This chapter provides an overview of the clinical evidence of Parkinsonism and cognitive impairments associated with primary mitochondrial disorders and nuclear-encoded defects in genes involved in mitochondrial DNA maintenance. We review three decades of research implicating mitochondrial involvement at the heart of disease progression and discuss the data from human post-mortem studies, which provide evidence of mitochondrial dysfunction and molecular changes in mtDNA quality and quantity in idiopathic Parkinson’s disease, primary mitochondrial and POLG-related disorders. We also discuss the mechanistic insights gained from transgenic animal models.