Cassel Raphaelle, Lorenc Félicie, Bombardier Aurélie, DE Tapia Claudia, Dieterle Stéphane, Gouveia Roque Cláudio, Jackson Christopher A, Stuart-Lopez Geoffrey, Rouaux Caroline, Guillot Simon J, Birling Marie-Christine, Kessler Pascal, Grassano Maurizio, Traynor Bryan, Chio Adriano, Roy Raju, Shorter James, Waldron Fergal M, Gregory Jenna M, Phatnani Hemali, Dupuis Luc, Megat Salim
Université de Strasbourg, Inserm, Strasbourg Translational Neuroscience and Psychiatry, UMR-S1329, Centre de Recherches en Biomédecine; Strasbourg, France.
Center for Genomics of Neurodegenerative Disease, New York Genome Center, 101 Avenue of the Americas, New York, NY 10013, USA.
medRxiv. 2025 Jun 17:2025.06.16.25329673. doi: 10.1101/2025.06.16.25329673.
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 in ALS-bi. Carriers of protein-truncating 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.
认知和行为障碍影响多达一半的肌萎缩侧索硬化症（ALS）患者，但其分子起源仍未得到解决。在此，我们确定RNA结合蛋白FUS在皮质神经元中的错误定位是患有认知障碍的ALS患者（ALS-ci）的一个决定性特征。FUS在成年小鼠皮质投射神经元中的选择性错误定位足以引发类似ALS-ci和伴有行为障碍的ALS（ALS-bi）的表型，包括社交缺陷和神经退行性变。单核转录组学揭示了在这些小鼠和ALS-ci患者中下调的保守的FUS依赖基因网络。该调控子富含ALS遗传风险因素，并新发现与ALS-bi有关。携带蛋白质截短变体的个体表现出行为异常、额颞叶萎缩以及与痴呆相关的生物标志物水平升高。这些发现确定了ALS中认知和行为功能障碍的神经元内在机制，并将FUS错误定位及其下游基因网络指定为治疗靶点。
