Title: Unveiling mitochondrial dysfunction in fragile X syndrome
Legend: Left – Microscope images compare neurons with normal or mutated fragile X gene. With the mutation, mitochondria show shorter and fail to join together. Right – Models for FMRP regulation of mitochondrial fusion and neuronal maturation. FMRP physiologically regulates HTT and mitochondrial fusion in neuronal maturation. Deficits of HTT, mitochondrial fusion and neuronal maturation contribute to FXS.
Citation: Shen M, Wang F, Li M, Sah N, Stockton ME, Tidei JJ, Gao Y, Korabelnikov T, Kannan S, Vevea JD, Chapman ER, Bhattacharyya A, van Praag H, Zhao X. (2019). Reduced mitochondrial fusion and Huntingtin levels contribute to impaired dendritic maturation and behavioral deficits in Fmr1-mutant mice. Nature Neuroscience, 22(3):386-400. doi: 10.1038/s41593-019-0338-y.
Abstract: Fragile X syndrome results from a loss of the RNA-binding protein fragile X mental retardation protein (FMRP). How FMRP regulates neuronal development and function remains unclear. Here we show that FMRP-deficient immature neurons exhibit impaired dendritic maturation, altered expression of mitochondrial genes, fragmented mitochondria, impaired mitochondrial function, and increased oxidative stress. Enhancing mitochondrial fusion partially rescued dendritic abnormalities in FMRP-deficient immature neurons. We show that FMRP deficiency leads to reduced Htt mRNA and protein levels and that HTT mediates FMRP regulation of mitochondrial fusion and dendritic maturation. Mice with hippocampal Htt knockdown and Fmr1-knockout mice showed similar behavioral deficits that could be rescued by treatment with a mitochondrial fusion compound. Our data unveil mitochondrial dysfunction as a contributor to the impaired dendritic maturation of FMRP-deficient neurons and suggest a role for interactions between FMRP and HTT in the pathogenesis of fragile X syndrome.
About the Lab: Research in the Zhao laboratory focuses on understanding the molecular mechanisms that regulate neural stem cells and neurodevelopment with the goal of applying this knowledge for the treatment of neurological disorders and injuries. Neurodevelopmental disorders are a highly heterogeneous constellation of disorders, both in terms of etiology and clinical manifestations. Using neural stem cells as model systems, the lab is investigating the molecular mechanisms that regulate neuronal development during the postnatal period and their implications in human neurodevelopmental disorders such as Rett syndrome, autism, and fragile X syndrome.