The proteasome is the major proteolytic system in the cytoplasm and nuclei of eukaryotic cells. The conserved Blm10/PA200 activators bind to the proteasome core particle gate and facilitate peptide and protein turnover in vitro. The ubiquitin proteasome system (UPS) has been implicated in the maintenance of mitochondrial structural dynamics and homeostasis.
We provided evidence for an additional regulatory function of the proteasome in mitochondrial homeostasis, mediated by the proteasome activator Blm10. We demonstrated that the regulated turnover of the mitochondrial fission protein Dnm1 mediated by Blm10-proteasomes provides a cytoprotective function under conditions that induce mitochondrial stress.
The mechanistic details of proteasome dysfunction in Huntington’s disease (HD) are unclear. It has been proposed that the proteasomes may become clogged by the aggregated protein fragments, leading to impaired UPS function. Recent reports also demonstrate that imbalanced mitochondrial dynamics is a crucial event underlying the pathology of HD-induced neurotoxicity. For instance, mutant huntingtin (mHtt) physically interacts with Drp1 (mammalian ortholog of Dnm1) and stimulates its GTPase activity causing mitochondrial fragmentation and neuronal cell death. We propose that upregulation of PA200 might provide a neuroprotective function through the regulated degradation of Drp1and is involved in the altered mitochondrial dynamics and function during the development of HD.
We have shown that loss of BLM10/PA200 upon expression of mHtt leads to a severe growth defect, increased aggregate formation of mHtt and excessive mitochondrial fragmentation in yeast.
Furthermore, we generated stable PA200 knock-down SH SY5Y cell lines (shPA200) to establish a cellular model for HD.
Drp1 is stabilized in shPA200 cells upon expressing different lengths of mHtt compared to the dramatically decreased Drp1 in the control. In addition, we have demonstrated that expression of different lengths of mHtt in shPA200 cells caused increased aggregates formation of mHtt.
Our results lead to speculate that PA200 has a regulatory function while HD progresses through its impact on Drp1 turnover.