ALS-related FUS mutations alter axon growth in motoneurons and affect HuD/ELAVL4 and FMRP activity

Mutations in the RNA-binding protein (RBP) FUS have been genetically associated with the motoneuron disease amyotrophic lateral sclerosis (ALS). Using both human induced pluripotent stem cells and mouse models, we found that FUS-ALS causative mutations affect the activity of two relevant RBPs with important roles in neuronal RNA metabolism: HuD/ELAVL4 and FMRP. Mechanistically, mutant FUS leads to upregulation of HuD protein levels through competition with FMRP for HuD mRNA 3’UTR binding. In turn, increased HuD levels overly stabilize the transcript levels of its targets, NRN1 and GAP43. As a consequence, mutant FUS motoneurons show increased axon branching and growth upon injury, which could be rescued by dampening NRN1 levels. Since similar phenotypes have been previously described in SOD1 and TDP-43 mutant models, increased axonal growth and branching might represent broad early events in the pathogenesis of ALS.

Case Report: Association of a Variant of Unknown Significance in the FIG4 Gene With Frontotemporal Dementia and Slowly Progressing Motoneuron Disease: A Case Report Depicting Common Challenges in Clinical and Genetic Diagnostics of Rare Neuropsychiatric and Neurologic Disorders

BackgroundModern genetics have in many ways revolutionized clinical routine and have, for instance, shown that formerly distinct disease entities relate to common pathogenic mutations. One such example is the connection between dementia and amyotrophic lateral sclerosis (ALS) in a continuous disease spectrum affirmed by the discovery of shared mutations.Case ReportWe describe a new variant in the FIG4 gene in a patient with slowly progressing frontotemporal dementia (FTD) and probable primary lateral sclerosis (PLS). The patient initially showed depressive symptoms and global cognitive deficits. Severe difficulties with language and hallucinations became clearer as the disease progressed. Nuclear medicine imaging and cerebrospinal fluid (CSF) biomarkers were not specific for defined categories of dementia, but neuropsychological testing and clinical features finally led to an allocation of the syndrome to the non-fluent variant of primary progressive aphasia (nfv PPA). Because of increasing limb weakness and bulbar symptoms, motoneuron disease in the form of PLS was diagnosed, strongly supported by elevated CSF neurofilament and electrophysiologic assessments. The detected variant in the FIG4 gene is described as pathogenic or likely pathogenic in common databases and reported once in the literature. While the phenotype of our patient fits the description of FIG4-associated disease in literature, we consider the present variant as VUS in this case.ConclusionWe describe a variant in the FIG4 gene in a patient with slowly progressing FTD and PLS. Mutations in the FIG4 gene have been associated with ALS and PLS; however, this exact mutation was not reported in ALS or PLS patients before. The case illustrates generic diagnostic challenges in patients presenting with genetic variants that offer an explanation for otherwise uncommon symptom combinations but yet are of unknown significance.

RNA-binding protein network alteration causes aberrant axon branching and growth phenotypes in FUS ALS mutant motoneurons

ABSTRACTMutations in RNA-binding proteins (RBPs) have been genetically associated with the motoneuron disease Amyotrophic Lateral Sclerosis (ALS). Using both human induced Pluripotent Stem Cells and mouse models, we found that FUS-ALS causative mutations have a profound impact on a network of RBPs, including two relevant factors with important roles in neuronal RNA metabolism: HuD and FMRP. Mechanistically, cytoplasmic localization of mutant FUS leads to upregulation of HuD levels through competition with FMRP for HuD 3’UTR binding. In turn, increased HuD levels overly stabilize the transcript levels of its targets, NRN1 and GAP43. As a consequence, mutant FUS motoneurons show altered axon branching and growth upon injury. Abnormal axon branching and regrowth in FUS mutant motoneurons could be rescued by dampening NRN1 levels. Since similar phenotypes have been previously described in SOD1 and TDP-43 mutant models, aberrant axonal growth and branching might represent broad early events in the pathogenesis of ALS.