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.

The main goal of this review is to provide an updated overview of the involvement of the RNA-binding protein (RBP) HuD, encoded by the ELAVL4 gene, in nervous system development, maintenance, and function, and its emerging role in nervous system diseases. A particular focus is on recent studies reporting altered HuD levels, or activity, in disease models and patients. Substantial evidence suggests HuD involvement in Parkinson’s disease (PD), Alzheimer’s disease (AD), and amyotrophic lateral sclerosis (ALS). Interestingly, while possible disease-causing mutations in the ELAVL4 gene remain elusive, a common theme in these diseases seems to be the altered regulation of HuD at multiple steps, including post-transcriptional and post-translational levels. In turn, the changed activity of HuD can have profound implications for its target transcripts, which are overly stabilized in case of HuD gain of function (as proposed in PD and ALS) or reduced in case of decreased HuD binding (as suggested by some studies in AD). Moreover, the recent discovery that HuD is a component of pathological cytoplasmic inclusion in both familial and sporadic ALS patients might help uncover the common molecular mechanisms underlying such complex diseases. We believe that deepening our understanding of the involvement of HuD in neurodegeneration could help developing new diagnostic and therapeutic tools.

Mutations 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.