Emerging Roles for the RNA-Binding Protein HuD (ELAVL4) in Nervous System Diseases

Abstract

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.

The molecular genetics of nELAVL in brain development and disease

“…ELAVL4 has been associated with various neurological disorders such as ALS, Alzheimer’s disease, and Parkinson’s disease through either genetic or cellular mechanisms, and this evidence is nicely reviewed in Silvestri et al 2022 [ 74 ]. The genetic studies have analysed signals associated with affection status or age-of-onset of Parkinson’s disease, with several common variants genotyped using SNP microarrays.…”

Evaluation of the concentration of growth associated protein-43 and glial cell-derived neurotrophic factor in degenerated intervertebral discs of the lumbosacral region of the spine

“… 10 , 11 Once transcription is complete, the resulting GAP-43 mRNA is stabilized by a neuron-specific RNA-binding protein (HuD). 12 There is evidence that HuD expression increases during brain development, neural regeneration, and learning, indicating that it has a stabilizing role in the maintenance of GAP-43 mRNA overexpression during neurodevelopmental processes in hippocampal dentate granule cells, neurons in the lateral amygdala, and layer V of the neocortex. 13 In contrast, the amino acid sequence of GAP-43 lacks membrane-spanning domains and glycosylation sites.…”

HuD (ELAVL4) gain-of-function impairs neuromuscular junctions and induces apoptosis inin vitroandin vivomodels of amyotrophic lateral sclerosis

“…A direct consequence of HuD upregulation in FUS mutant iPSC-derived MNs and mouse spinal cord is an increase in the levels of its targets, including Neuritin1 (NRN1; also known as cpg15) and GAP43 (Garone et al, 2021). HuD plays key roles during nervous system development and recent evidence points to its possible involvement in neurodegenerative processes as well (Bronicki and Jasmin, 2013;Dell'Orco et al, 2021;Silvestri et al, 2022). In this work we aimed to assess if HuD dysregulation could underlie neuromuscular junctions (NMJs) defects in the context of ALS.…”