Omic profiling of vulnerable synapses in age-related neurodegeneration - Many studies implicate mitochondrial dysfunction as a key contributor to age-related neurodegenerative diseases, including Parkinson’s disease (PD). Previously published gene expression analyses from laser-captured dopaminergic (DA) neurons from the substantia nigra of preclinical patients found a decrease in genes associated with mitochondrial respiration. However, the implications of this decrease in mitochondrial genes and its link to disease progression and pathology are still unknown. A decrease in a large number of nuclearly-encoded mitochondrial genes suggests that a central regulator of gene expression is impaired; in fact, most affected genes are putative targets for the transcription factor estrogen-related receptor gamma (ERRg), a transcription factor that has not been well-characterized in neurons. Here, we determine the dependence of DA neurons on ERRg for gene expression, survival, and regulation of motor function and explore whether cell type-specific deletion of ERRg predisposes DA neurons to alpha-synuclein-mediated neurotoxicity. Preliminary experiments determined that removal of ERRg from DA neurons influenced gene expression and motor function and rendered DA neuron processes more vulnerable to loss with alpha-synuclein pre-formed fibril (PFF) exposure. This led to the hypothesis that ERRg has a role in promoting synaptic viability in the presence of alpha-synuclein. Experiments in the predoctoral portion will use bioinformatics, transcriptional assays and novel, cell type-specific proteomic techniques to reveal the ERRg-dependent pathways by which nigral neurons regulate mitochondrial and synaptic function and whether these pathways can be leveraged to prevent or delay disease-related synaptic loss. Synaptic abnormalities also occur in the cortical-hippocampal circuit with age, contributing to cognitive decline; however, the transcriptional and proteomic changes which contribute to this decline have not been delineated in a cell type-specific way. In the postdoctoral phase of this award, the applicant will apply the technical knowledge acquired during the predoctoral stage to understand the aging circuits in the hippocampus and cortex using bioinformatics and novel cell type-specific proteomic techniques. This work has the potential to reveal how synapses change with age, with the long-term goal of developing strategies to counteract cognitive decline. In addition to a rigorously designed and innovative research strategy, this application involves a strong training plan specifically designed to promote the future success of the applicant as an independent research scientist in neuroscience and aging. The plan includes exposure to emerging themes and techniques in aging research, opportunities for development in presentation skills and manuscript preparation, co-sponsorship from principal investigators with strong training records and commitment to graduate training, a unique combination of academic and drug discovery expertise, and training in the responsible conduct of research. Altogether, the combined research and training plans position the trainee to become an independent and productive member of the neuroscience aging research community.
