Role of Elevated Diet-linked TOR Activity and Protein Synthesis in Parkinson's Disease Neurodegeneration

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 DESCRIPTION (provided by applicant): I am a young neuroscientist with doctoral training in the biology of aging and post-doctoral training in molecular neurodegeneration research from Johns Hopkins University. My long-term career goal is to become an independent investigator focusing on mechanisms of neurodegeneration in Parkinson's disease (PD) related to the aging process and mRNA translation. My goal over the next five years is to acquire additional knowledge and expertise in translation research and methodology in order to probe the role of altered mRNA translation in PD neurodegeneration. To attain these goals, I have assembled a team of outstanding mentors, and together we have developed a structured training program that includes substantial hands-on research training in translational profiling experiments and bioinformatics analysis of deep sequencing data as well as participation in lab presentations, departmental seminars, formal courses, international scientific meetings, and grant writing training. The prevalence of PD, which affects approximately 1% of the population over 60, is projected to double by 2040 with increased human longevity. As aging is a clear risk factor for developing PD, mechanisms driving the aging process might be important in the progressive degeneration of dopamine neurons underlying motor dysfunction in PD. We discovered that mutations in LRRK2 (leucine-rich repeat kinase 2) cause PD- related phenotypes in human neurons and Drosophila by increasing bulk mRNA translation. Compelling evidence from dietary restriction studies suggests that life span and other aging parameters are affected by the activity of TOR (target of rapamycin), which regulates organismal homeostasis in part through governing mRNA translation. A key unresolved question is whether the metabolic influence on mRNA translation through TOR signaling can drive dopamine neuron degeneration in aging organisms. My mentors and I have designed a series of studies to address this question and to also identify critical translational targets and mechanistic pathways linking excess mRNA translation through diet or G2019S LRRK2 expression to dopamine neuron degeneration. The research aims of the Application are to (i) determine if excess dietary amino acid consumption causes age-related dopamine neuron degeneration and locomotor dysfunction through elevated TOR activity (ii) determine if reduced amino acid consumption blocks these phenotypes in aged G2019S LRRK2 transgenic flies through attenuating TOR activity (iii) determine the effects of excess amino acid consumption and G2019S LRRK2 on the mRNA translation profile of vulnerable dopamine neurons relative to other neurons (iv) delineate the role of G2019S LRRK2 and diet-linked TOR translational targets in neurodegeneration. The use of Drosophila in these studies will allow for rapid and high throughput disease modeling in an organism that recapitulates the age-related loss of dopamine neurons and locomotor dysfunction caused by PD-linked mutations. Collectively, these studies will probe the intersection of mRNA translation, aging and neurodegenerative disease and lead to the identification of potential therapeutic targets.