Two patients with a slowly progressive and severe motor apraxia are presented. In one case, there was only apraxia; in the other there was moderate memory disturbance and a mild decline of global intellectual ability, suggesting a more widespread cognitive dysfunction. In this second case, recognition of the correct use of objects was also severely impaired, suggesting a disturbance of motor knowledge. In both cases, apraxia was asymmetrical, and associated with a contralateral atrophy of the upper parietal cortex, suggesting a differential involvement of separate action systems for each hand.
The mitochondrial unfolded protein response (UPRmt) has emerged as a predominant mechanism that preserves mitochondrial function. Consequently, multiple pathways likely exist to modulate UPRmt. We unexpectedly discovered that the tRNA processing enzyme, homolog of ELAC2 (HOE-1), is central to UPRmt regulation in Caenorhabditis elegans. We find that nuclear HOE-1 is necessary and sufficient to robustly activate UPRmt. We show that HOE-1 acts via transcription factors ATFS-1 and DVE-1 that are crucial for UPRmt. Mechanistically, we show that HOE-1 likely mediates its effects via tRNAs, as blocking tRNA export prevents HOE-1-induced UPRmt. Interestingly, we find that HOE-1 does not act via the integrated stress response, which can be activated by uncharged tRNAs, pointing towards its reliance on a new mechanism. Finally, we show that the subcellular localization of HOE-1 is responsive to mitochondrial stress and is subject to negative regulation via ATFS-1. Together, we have discovered a novel RNA-based cellular pathway that modulates UPRmt.
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