Mechanisms of mitochondrial genome integrity in familial and idiopathic Parkinson's disease

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ABSTRACT Parkinson’s disease (PD) is the most common neurodegenerative movement disorder and over ten million people worldwide are living with PD. To date, treatments are only symptomatic; they do not alter the inexorable progression of the disease. The most common cause of familial and idiopathic PD are mutations in leucine-rich repeat kinase 2 (LRRK2). LRRK2-associated and idiopathic PD demonstrate mitochondrial impairment, however our understanding of the molecular underpinnings of mitochondrial dysfunction in PD is limited. In our efforts to understand the underlying mechanisms driving mitochondrial dysfunction, we found that mitochondrial DNA damage is a shared phenotype amongst both LRRK2-associated and idiopathic PD. Unrepaired mitochondrial DNA damage can have major adverse cellular effects, impacting genetic and protein instability, compromising bioenergetic function, increasing reactive oxygen species, and triggering cell death. Recent preliminary studies by the Sanders lab has found that blocking kinase activity of ATM (a kinase that functions to sense, signal and promote repair of DNA damage) rescues PD-induced mitochondrial DNA damage. We further observed that ATM is activated and initiates the DNA damage response pathway. Interestingly, mitochondrial DNA repair capacity is impaired with a concomitant increase in specific mitochondrial oxidative DNA lesions. Our central hypothesis is that dysfunctional LRRK2 triggers the ATM-mediated DNA damage response pathway, which impairs mitochondrial DNA repair capacity, leading to an increase in mitochondrial DNA damage, ultimately promoting downstream pathogenic PD cascades. We will test this hypothesis with three specific aims that integrate molecular, biochemical and cellular techniques using established neuronal and murine PD models. Aim 1 will determine the molecular nature of the mitochondrial DNA damage and the dependency on LRRK2 kinase activity. Aim 2 will define the cellular mechanism(s) by which mitochondrial DNA damage accumulates in PD. Aim 3 will determine the contribution of ATM to PD-associated phenotypes. This project will advance our understanding of LRRK2 function in maintaining mitochondrial homeostasis. Further, preclinical testing may establish ATM as a viable therapeutic target and lay the foundation for the development of neuroprotective PD therapeutic strategies.