The role of Mitofusin (Mfn) in the pathogenesis of Parkinson’s disease and myopathy/frontotemporal dementia
- Author(s): Zhang, Ting;
- Advisor(s): Guo, Ming;
- et al.
As life expectancy prolongs, the incidence of neurodegenerative diseases continues to rise. The pathogenesis of neurodegenerative diseases is poorly understood and there is no effective long-term therapy. This thesis focus on two neurodegenerative disease: Parkinson’s disease (PD), the second most common neurodegenerative disease and inclusion body myopathy, Paget disease with frontotemporal dementia (IBMPFD) caused by Valosin-containing protein (VCP) mutants. Recent studies accentuate the key role of mitochondrial dysfunction in disease-onset. Mitochondrial fusion/fission is critical for mitochondrial integrity with Mitofusins (Mfn) control the initial step of fusion. We found that Mitofusins are key targets in both Parkinson’s disease and in disease by VCP mutants.
Mutations in PTEN-induced putative kinase 1 (PINK1) and parkin cause autosomal recessive PD. Genetic studies indicate PINK1 and parkin function in a common pathway and negatively regulate Mfn. In chapter two, we identify VCP as a suppressor for PINK1 and parkin mutants and its suppression is achieved through Mfn degradation. VCP missense mutations cause IBMPFD and other neurodegenerative disorders. The pathological mechanism of IBMPFD is not clear and there is no cure. we generated an in vivo IBMPFD model in Drosophila, which recapitulates disease pathologies in human patients; we demonstrated common VCP disease mutants act as hyperactive alleles and found that VCP inhibitors reverse the disease pathology in in vivo disease models as well as in patients’ fibroblasts. Our results strongly suggest VCP inhibitors have therapeutic value.
Mitofusins are key substrates of ubiquitin E3 ligase Parkin. Yet the exact mechanism of the ubiquitination is not well-understood. In chapter three, we identified critical lysine sites for Mitofusin ubiquitination by Parkin in Drosophila as well as in mammalian cells. Flies harboring mutated lysine sites display severe tissue defects. Parkin-mediated mitophagy plays a major role in mitochondrial quality control. Lysine mutants delay Parkin-mediated degradation of Mitofusins and mitophagy. Our results uncover the important regulatory role of Mitofusins in mitochondrial quality control and tissue health.
Together, our work demonstrates that utilizing Drosophila and human cells, we could establish reliable in vivo and in vitro models of neurodegenerative disease, unravel novel disease mechanism and identify therapy for these devastating diseases.