FUS Mislocalization Rewires a Cortical Gene Network to Drive Cognitive and Behavioral Impairment in ALS
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Cognitive and behavioral impairment affects up to half of individuals with amyotrophic lateral sclerosis (ALS), but their molecular origin remains unresolved. Here, we identify mislocalization of the RNA-binding protein FUS in cortical neurons as a defining feature in ALS patients with cognitive impairment (ALS-ci). Selective mislocalization of FUS in adult cortical projection neurons in mice is sufficient to trigger ALS-ci– and ALS with behavioral impairment (ALS-bi)–like phenotypes, including deficits in sociability, and neurodegeneration. Single-nucleus transcriptomics reveal a conserved FUS-dependent gene network downregulated in these mice and ALS-ci patients. This regulon is enriched for ALS genetic risk factors and newly implicates FBXO16 in ALS-bi. Carriers of protein-truncating FBXO16 variants display behavioral abnormalities, frontotemporal atrophy, and increased levels of dementia-linked biomarkers. These findings define a neuron-intrinsic mechanism for cognitive and behavioral dysfunction in ALS and nominate FUS mislocalization and its downstream gene network as therapeutic targets.
Highlights
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Transcriptional fingerprint of FUS mislocalization is observed in cortical projection neurons of ALS patients
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FUS mislocalization leads to downregulation in cortical projection neurons of a cross-species conserved regulon shared with TDP43
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FUS mislocalization in adult cortical projection neurons is sufficient to trigger ALS related cognitive and behavioral impairment in mouse models
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FUS is mislocalized and the FUS regulon is downregulated in ALS patients with cognitive impairment
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The FUS regulon is enriched in genetic risk factors for cognitive and behavioral impairment in ALS
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Carriers of protein truncating variants of FBXO16 , one of the FUS regulon genes, display behavioral, imaging and biochemical markers of ALS with behavioral impairment.