Fragile X syndrome, the most common form of inherited intellectual disability, is caused most often by a lack of fragile X mental retardation protein (FMRP). However, the mechanism remains unclear and effective treatment is lacking. Here we show that a loss of FMRP leads to activation of adult neural stem cells (NSCs) and a subsequent reduction in neuronal production. We identified ubiquitin ligase MDM2 as a target of FMRP. FMRP regulates Mdm2 mRNA stability, and loss of FMRP results in elevated mRNA and MDM2 protein levels. We further found that increased MDM2 levels lead to reduced P53 in NSCs, which alters NSC proliferation and differentiation. Treatment with Nutlin-3, a small molecule undergoing clinical trials for cancer, specifically inhibits MDM2 and P53 interaction, and rescues the neurogenic and cognitive deficits in FMRP-deficient mice. Our data unveil a regulatory role for FMRP and a potential new treatment for fragile X syndrome.

Fragile X syndrome (FXS) is the most prevalent inherited intellectual disability, resulting from a loss of fragile X mental retardation protein (FMRP). Patients with FXS suffer lifelong cognitive disabilities, but the function of FMRP in the adult brain and the mechanism underlying age-related cognitive decline in FXS is not fully understood. Here, we report that a loss of FMRP results in increased protein synthesis of histone acetyltransferase EP300 and ubiquitination-mediated degradation of histone deacetylase HDAC1 in adult hippocampal neural stem cells (NSCs). Consequently, FMRP-deficient NSCs exhibit elevated histone acetylation and age-related NSC depletion, leading to cognitive impairment in mature adult mice. Reducing histone acetylation rescues both neurogenesis and cognitive deficits in mature adult FMRP-deficient mice. Our work reveals a role for FMRP and histone acetylation in cognition and presents a potential novel therapeutic strategy for treating adult FXS patients.

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 knock-down 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.

CRISPR/Cas9 guided gene-editing is a potential therapeutic tool, however application to neurodegenerative disease models has been limited. Moreover, conventional mutation correction by gene-editing would only be relevant for the small fraction of neurodegenerative cases that are inherited. Here we introduce a CRISPR/Cas9-based strategy in cell and animal models to edit endogenous amyloid precursor protein (APP) at the extreme C-terminus and reciprocally manipulate the amyloid pathway, attenuating APP-β-cleavage and Aβ production, while up-regulating neuroprotective APP-α-cleavage. APP N-terminus and compensatory APP-homologues remain intact, with no apparent effects on neurophysiology in vitro. Robust APP-editing is seen in human iPSC-derived neurons and mouse brains with no detectable off-target effects. Our strategy likely works by limiting APP and BACE-1 approximation, and we also delineate mechanistic events that abrogates APP/BACE-1 convergence in this setting. Our work offers conceptual proof for a selective APP silencing strategy.

In the central nervous system, oligodendrocytes produce myelin sheaths that enwrap neuronal axons to provide trophic support and increase conduction velocity. New oligodendrocytes are produced throughout life through a process referred to as oligodendrogenesis. Oligodendrogenesis consists of three canonical stages: the oligodendrocyte precursor cell (OPC), the premyelinating oligodendrocyte (preOL), and the mature oligodendrocyte (OL). However, the generation of oligodendrocytes is inherently an inefficient process. Following precursor differentiation, a majority of premyelinating oligodendrocytes are lost, likely due to apoptosis. If premyelinating oligodendrocytes progress through this survival checkpoint, they generate new myelinating oligodendrocytes in a process we have termed integration. In this review, we will explore the intrinsic and extrinsic signaling pathways that influence preOL survival and integration by examining the intrinsic apoptotic pathways, metabolic demands, and the interactions between neurons, astrocytes, microglia, and premyelinating oligodendrocytes. Additionally, we will discuss similarities between the maturation of newly generated neurons and premyelinating oligodendrocytes. Finally, we will consider how increasing survival and integration of preOLs has the potential to increase remyelination in multiple sclerosis. Deepening our understanding of premyelinating oligodendrocyte biology may open the door for new treatments for demyelinating disease and will help paint a clearer picture of how new oligodendrocytes are produced throughout life to facilitate brain function.