Friday, May 9, 2025
5/9/2025
Synaptic Dysfunction and Energy Failure in Parkinson's Disease - Summary Parkinson’s disease (PD) is the second most common neurodegenerative disease. Loss of substantia nigra compacta (SNc) dopaminergic projections and decreased striatal dopamine levels are the characteristic features of PD. Emerging evidence suggest that synaptic dysfunction of dopamine neurons is an early event in the pathogenesis of PD occurring prior to the onset of symptoms. Mutations in the leucine-rich repeat kinase 2 (LRRK2) gene are the most prevalent causes of familial and sporadic PD, demonstrating an unprecedented significant role in PD pathogenesis. A transgenic mouse model with over-expression of human LRRK2- R1441G has been shown to recapitulate robust motor behavioral, neurochemical and pathological features of PD. At the level of pathology, the most robust phenotype is the axonopathy of the nigrostriatal dopaminergic projection, accompanied by age-dependent hyperphosphorylated tau and DA transmission deficits. Both genetic and environmental causes of PD have highlighted the importance of mitochondrial dysfunction in the pathogenesis of PD. Mitochondrial trafficking is critical for neurons’ survival and functions including synaptic neurotransmission. However, mitochondrial trafficking and dynamics in mutant LRRK2 associated-PD has not been well studied. We find that the mitochondrial oxidant stress is elevated in the LRRK2-R1441G mutants whereas mitochondrial respiration and mitochondrial ATP synthesis is significantly reduced. In addition, our preliminary studies uncovered early and defining features in mitochondria trafficking and dynamics impairment: frangmented mitochondria in SNc dopamine neurons and terminals, increased cytosolic calcum levels, tau hyperphosphorylation, and decreased anterograde healthy mitochondrial transport. We hypothesize that R1441G mutation impairs mitochondria trafficking and dynamics via dysregulation of Miro1 and calcium homeostasis and pathologic tau accumulation that ultimately result in synaptic dysfunction, energy failure and axonal degeneration. We will utilize a combination of two-photon imaging (2PLSM) and electrophysiology recording in living brain slices, and mouse genetics to uncover mechanisms underlying DAergic transmission deficits and axonal degeneration in PD.
HHS’ Tracking Accountability in Government Grants System (TAGGS) website provides access to detailed descriptions of grants, loans, aggregated direct payments and other types of financial assistance awarded by the HHS Operating Divisions (OPDIVs) and the Office of the Secretary Staff Divisions (STAFFDIVs).