Accumulation of alpha-synuclein (αSyn) causes degeneration of dopaminergic (DA) and non-DA neurons in Parkinson’s disease (PD) and Dementia with Lewy Bodies (DLB). αSyn also contributes to the fibrilization of amyloid-β and tau, two key proteins in Alzheimer’s disease (AD), which suggests a key role for αSyn toxicity in neurodegeneration. Thus, it is important to elucidate downstream effects and the factors promoting the toxic conversion of αSyn, towards understanding the pathogenesis of and developing disease-modifying therapies for synucleinopathies. In PD and DLB, pathological αSyn proteins enrich in mitochondria of vulnerable brain regions, where to induce mitochondrial bioenergetic defects and production of reactive oxygen species. Despite evidence suggests that αSyn-mitochondrial interactions may play a causal role in PD and DLB, the field lacks a detailed understanding of the mechanisms by which αSyn 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 proteins within mitochondria. They also 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. Our recent work showed, for the first time, that the protein level of ClpP, a mitochondrial matrix protease induced during UPRmt activation, was decreased in neurons expressing αSyn wildtype (WT) or A53T mutant, in brains of mice carrying A53T mutant, and in the Substantia Nigra of PD patients. The mRNA level of ClpP remained unchanged, suggesting a transcriptional independent effect. Preliminary study further found that the protein level of ClpP and not other mitochondrial proteases, decreased in the cortex of patients with DLB and mice expressing human Thy1-αSyn. These results suggest that a decrease in ClpP is a common event implicated in the pathogenesis of both PD and DLB. Whereas silencing ClpP in neurons increased a load of unfolded proteins in the mitochondria, reduced mitochondrial bioenergetic activity and increased cell death; overexpressing ClpP abolished αSyn-induced oxidative stress in cultured cells, and attenuated αSyn hyper-phosphorylation and behavioral abnormality in αSyn A53T mice. Notably, we found that αSyn bound to ClpP and suppressed ClpP peptidase activity, whereas genetic manipulation of ClpP influenced the assembly of non-toxic αSyn tetramers that resist aggregation. Thus, our pilot findings highlight a previously unidentified interdependence between pathological αSyn and ...