Parkinson’s disease (PD) is a complex neurodegenerative disorder that is both sporadic and familial. Mutations in parkin are the most common cause of autosomal recessive PD. In sporadic PD dopaminergic, several pathways (including oxidative and nitrosative stress as well as c-Abl phosphorylation) result in inhibition of parkin. Thus, loss of parkin function is elemental to both familial and sporadic PD. Parkin is an E3 ligase, this loss of function leads to accumulation of the substrates, AIMP2 and PARIS. We have found that AIMP2 expression leads to age dependent DA neurodegeneration due to parthanatos. And PARIS expression may lead to loss of mitochondrial quality control that promotes neurodegeneration.
Project 1, in collaboration with Project 2
, Core C
and Core D
, proposes to investigate whether parkin inactivation in sporadic PD by nitrosative/oxidative stress, and c-Abl activation leads to parkin phosphorylation and inactivation causing the accumulation of parkin substrates, loss of mitochondrial quality control and toxicity in parallel with alpha-synuclein aggregation which leads to mitochondria dysfunction and subsequent toxicity. In specific Aim 1 they will explore the interrelationship of PARIS and mitochondrial dysfunction caused by mutations in parkin. In specific Aim 2 the will explore the sequence of events activated by PARIS and AIMP2 accumulation in order to determine if and how these two proteins interact to initiate the cell death program, parthanatos. In specific Aim 3 they investigate whether parkin inactivation, PARIS and AIMP2 upregulation and PARP1 activation play a role in α-synuclein induced neurodegeneration. In specific Aim 4, state-of-the-art technology including deep sequencing and SILAM (stable isotope labeling by amino acids in mammals) will be deployed to identify genes and proteins that are regulated by adult conditional knockout of parkin and their relationship to PARIS induction with the goal of identify nodal points in the signal cascade of neurodegeneration that can provide new targets for the treatment of PD.
Ted M. Dawson (Principal Investigator)
Haisong Jiang (Research Staff)
Changqing Yuan (Research Staff)