FUS Mislocalization Rewires a Cortical Gene Network to Drive Cognitive and Behavioral Impairment in ALS
Cassel, R.; Lorenc, F.; Bombardier, A.; De Tapia, C.; Dieterle, S.; Gouveia-Roque, C.; Jackson, C. A.; Stuart-Lopez, G.; Rouaux, C.; Guillot, S. J.; Birling, M.-C.; Kessler, P.; Grassano, M.; Traynor, B. J.; Chio, A.; Roy, R.; Shorter, J.; Waldron, F. M.; Gregory, J. M.; Phatnani, H.; Dupuis, L.; Megat, S.
10.1101/2025.06.16.25329673 medRxivShow abstract
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. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=200 SRC="FIGDIR/small/25329673v1_ufig1.gif" ALT="Figure 1"> View larger version (57K): org.highwire.dtl.DTLVardef@ca1465org.highwire.dtl.DTLVardef@10105c1org.highwire.dtl.DTLVardef@20ea6corg.highwire.dtl.DTLVardef@fe7f80_HPS_FORMAT_FIGEXP M_FIG C_FIG HighlightsO_LITranscriptional fingerprint of FUS mislocalization is observed in cortical projection neurons of ALS patients C_LIO_LIFUS mislocalization leads to downregulation in cortical projection neurons of a cross-species conserved regulon shared with TDP43 C_LIO_LIFUS mislocalization in adult cortical projection neurons is sufficient to trigger ALS related cognitive and behavioral impairment in mouse models C_LIO_LIFUS is mislocalized and the FUS regulon is downregulated in ALS patients with cognitive impairment C_LIO_LIThe FUS regulon is enriched in genetic risk factors for cognitive and behavioral impairment in ALS C_LIO_LICarriers of protein truncating variants of FBXO16, one of the FUS regulon genes, display behavioral, imaging and biochemical markers of ALS with behavioral impairment. C_LI
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