Research Lab.
Extension no.32444
Participating professorMingli Hsieh
Research directionOur laboratory has been working on the characterization of Hsp27 and carbonic anhydrase related proteins in Spinocerebellar Ataxias and Myoclonus Epilepsy with Ragged Red Fibers (MERRF) disease models for the past five years. We have extensive experience in the investigation of endogenous and exogenous gene expression in disease cellular models.
By using a MERRF cybrid disease model (kindly provided by Dr. Yau-Huei Wei at Yang-Ming University), we have shown that Hsp27 and phosphorylated Hsp27 (p-Hsp27) play protective roles in the MERRF disease. We observed a significant decrease of Hsp27 in lymphoblastoid cells derived from a MERRF patient and in cybrid cells harboring MERRF A8344G mutation. In addition, we demonstrated that overexpression of wild type Hsp27, especially phosphomimicking-Hsp27 in mutant MERRF cybrids significantly decreased cell death under staurosporine (STS) treatment, suggesting a protective function of p-Hsp27 in cells harboring MERRF A8344G mutation. Evidenced by the decreased levels of Hsp27 upon proteasome inhibitor, starvation and rapamycin treatments, and the accumulation of Hsp27 upon lysosomal inhibitor treatment; Hsp27 may be degraded by the autophagic pathway. Interestingly, the turnover of p-Hsp27 was mediated through proteasome degradation pathway. In addition, the increased formation of LC3-II and autophagosomes was found in MERRF cybrids under the basal condition, indicating a constitutively-activated autophagic pathway. It may explain, at least partially, the faster turn-over of Hsp27 in MERRF cybrids. Our study provided understanding that Hsp27 and p-Hsp27 are degraded through different pathways and the altered protein degradation may play an important role in the disease progression. We suggest that regulation of Hsp27 and the autophagic pathway might develop therapeutic solutions for MERRF disease in the future. Currently, we concentrate on the characterization of carbonic anhydrase related proteins in the neuromuscular diseases like Spinocerebellar Ataxias and mitochondrial diseases.
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