Alpha-synuclein (αSyn) misfolding is associated with several devastating neurodegenerative disorders, including Parkinson's disease (PD). In yeast cells and in neurons αSyn accumulation is cytotoxic, but little is known about its normal function or pathobiology. The earliest defect following αSyn expression in yeast was a block in endoplasmic reticulum (ER)-to-Golgi vesicular trafficking. In a genomewide screen, the largest class of toxicity modifiers were proteins functioning at this same step, including the Rab guanosine triphosphatase Ypt1p, which associated with cytoplasmic αSyn inclusions. Elevated expression of Rab1, the mammalian YPT1 homolog, protected against αSyn-induced dopaminergic neuron loss in animal models of PD. Thus, synucleinopathies may result from disruptions in basic cellular functions that interface with the unique biology of particular neurons to make them especially vulnerable.Parkinson's disease (PD) is the second most common neurodegenerative disorder (1,2). Accruing evidence points to a causative role for the presynaptic protein alpha-synuclein (αSyn) in PD pathogenesis. αSyn is a major constituent of Lewy Bodies-cellular inclusions that are the hallmark pathological feature of PD and other neurodegenerative disorders collectively

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To better understand the response to mitochondrial dysfunction, we examined the mechanism by which Activating Transcription Factor associated with Stress-1 (ATFS-1) senses mitochondrial stress and communicates with the nucleus during the mitochondrial unfolded protein response (UPRmt). We found that the key point of regulation was the mitochondrial import efficiency of ATFS-1. In addition to a nuclear localization sequence, ATFS-1 has an amino-terminal mitochondrial targeting sequence, which was essential for UPRmt repression. Normally, ATFS-1 is imported into mitochondria and degraded. However, during mitochondrial stress, import efficiency was reduced allowing a percentage of ATFS-1 to accumulate in the cytosol and traffic to the nucleus. Our results show that cells monitor mitochondrial import efficiency via ATFS-1 to coordinate the level of mitochondrial dysfunction with the protective transcriptional response.

The cellular response to unfolded and misfolded proteins in the mitochondrial matrix is poorly understood. Here, we report on a genome-wide RNAi-based screen for genes that signal the mitochondrial unfolded protein response (UPR(mt)) in C. elegans. Unfolded protein stress in the mitochondria correlates with complex formation between a homeodomain-containing transcription factor DVE-1 and the small ubiquitin-like protein UBL-5, both of which are encoded by genes required for signaling the UPR(mt). Activation of the UPR(mt) correlates temporally and spatially with nuclear redistribution of DVE-1 and with its enhanced binding to the promoters of mitochondrial chaperone genes. These events and the downstream UPR(mt) are attenuated in animals with reduced activity of clpp-1, which encodes a mitochondrial matrix protease homologous to bacterial ClpP. As ClpP is known to function in the bacterial heat-shock response, our findings suggest that eukaryotes utilize component(s) from the protomitochondrial symbiont to signal the UPR(mt).