Friday, April 19, 2024
4/19/2024
Project Summary/Abstract Mutations in the PTEN induced kinase 1 (PINK1) gene cause autosomal recessive Parkinson's disease (PD). The main pathological hallmarks of PD are loss of dopamine neurons in the substantia nigra pars compacta, which are required for normal movement, and the formation of a-synuclein rich aggregates termed Lewy body inclusions. Preliminary data from our lab and published reports on PINK1 knockout (KO) rats have demonstrated that the rats have mitochondrial dysfunction, locomotor deficits, loss of neurons in the substantia nigra and locus coeruleus, and a-synuclein aggregates in different brain regions including the substantia nigra, striatum, and cortex. PINK1 is a mitochondrial targeted kinase involved in the clearance of damaged mitochondria. In neurons, mitochondria are predominantly located in the pre-synaptic terminal, where they provide the energy needed for vesicle movement and synaptic transmission. a- Synuclein is also predominantly localized to the pre-synaptic terminal where it has reported functions in movement of synaptic vesicles from the reserve pool to the readily releasable pool. Given the importance of both mitochondria and a-synuclein to synaptic transmission, and the effect of PINK1 deficiency on mitochondrial health and a-synuclein accumulation, it remains to be determined whether PINK1 KO rats have deficits in synaptic transmission. It is also unknown whether a-synuclein pathology is simply an end byproduct of the accumulation of damaged mitochondria or, whether it directly contributes to the observed pathological processes in PINK1 KO rats. Our preliminary findings, as well as published reports, have led us to the hypothesis that PINK1 deficiency leads to a-synuclein aggregation, which causes a cascade of synaptic dysfunction, locomotor abnormalities, and dopaminergic neuron loss. To determine a-synuclein's role in the pathophysiology of PINK1 KO rats, we will utilize a combination of electrophysiological, histological, biochemical and behavioral analyses. The results will indicate whether a-synuclein aggregation itself drives the observed pathology, providing an answer to the importance of targeting a-synuclein interventions to halt or slow PD progression.
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).
