Parkinson's disease (PD) is characterized by a preferential loss of midbrain dopaminergic (DA) neurons. Although the mechanisms underlying PD remain elusive, ?-Synuclein (?Syn) accumulation and mitochondrial deficiency are two major changes in the brains of patients with PD. While missense mutations of ?Syn cause an early-onset autosomal dominant familial form of PD, abnormal accumulation of ?Syn is associated with sporadic PD. ?Syn contains a cryptic mitochondrial targeting sequence and is enriched in mitochondria in the striatum and substantial nigra (SN) relative to other brain regions. Pathological accumulation of ?Syn in the mitochondria of PD vulnerable brain regions is associated with mitochondrial bioenergetic defects and production of reactive oxygen species. Despite these observations showing that ?Syn-mitochondrial interactions may play a causal role in PD, the field lacks a detailed understanding of the mechanisms by which ?Syn abnormality and mitochondrial functional deficiency influence each other. To maintain normal mitochondrial health and function, cells employ a mitochondria-to-nucleus signaling pathway termed the mitochondrial unfolded protein response (UPRmt). The UPRmt monitors mitochondrial proteostasis through mitochondrial specific proteases and molecular chaperones, which facilitate folding and/or degradation of unfolded or misfolded proteins within mitochondria, and they communicate with the nucleus by retrograde signaling to activate the expression of peptide-folding related proteins. The UPRmt is an important defense mechanism for maintaining the quality of proteins within the mitochondria under stress. Defects in UPRmt have been linked to aging and neurodegeneration. Preliminary research found that the protein level of ClpP, a mitochondrial matrix protease induced during UPRmt activation, is selectively decreased in DA neurons stably expressing ?Syn wildtype (WT) or A53T mutant, and in brains of mice carrying A53T mutant. Moreover, the immunodensity of ClpP was greatly reduced in DA neurons of the SN in both ?Syn A53T transgenic mice and PD patient postmortem brains. Whereas silencing ClpP in DA neurons reduced mitochondrial bioenergetic activity and increased cell death, overexpressing ClpP abolished ?Syn-induced mitochondrial oxidative stress in cultured cells and attenuated behavioral abnormality in ?Syn A53T PD mice. Notably, we found that ?Syn WT and A53T mutant bound to ClpP and suppressed ClpP peptidase activity. Taken together, these preliminary findings have led us to formulate the central hypothesis that ?Syn causes mitochondrial bioenergetic defects and oxidative stress by suppressing ClpP and UPRmt, which results in ?Syn neuropathology. The significance of the proposed study is that a detailed characterization of the precise mechanism by which ?Syn affects mitochondrial function and neuronal survival will not only contribute to the basic understanding of disease pathogenesis, but also aid in the development of treatments for PD and other synucleinopathies.
?-Synuclein accumulation and mitochondrial deficiency are two major changes in the brains of patients with Parkinson's disease (PD), one of the most common neurodegenerative disorders. The proposed study seeks to better understand the molecular mechanisms by which ?-Synuclein causes mitochondrial dysfunction, and to reveal novel targets for developing therapeutics to treat PD.
