A Comprehensive Analysis of the Role of hnRNP A1 Function and Dysfunction in the Pathogenesis of Neurodegenerative Disease

Abstract

Heterogeneous nuclear ribonucleoprotein A1 (hnRNP A1) is a member of the hnRNP family of conserved proteins that is involved in RNA transcription, pre-mRNA splicing, mRNA transport, protein translation, microRNA processing, telomere maintenance and the regulation of transcription factor activity. HnRNP A1 is ubiquitously, yet differentially, expressed in many cell types, and due to post-translational modifications, can vary in its molecular function. While a plethora of knowledge is known about the function and dysfunction of hnRNP A1 in diseases other than neurodegenerative disease (e.g., cancer), numerous studies in amyotrophic lateral sclerosis, frontotemporal lobar degeneration, multiple sclerosis, spinal muscular atrophy, Alzheimer’s disease, and Huntington’s disease have found that the dysregulation of hnRNP A1 may contribute to disease pathogenesis. How hnRNP A1 mechanistically contributes to these diseases, and whether mutations and/or altered post-translational modifications contribute to pathogenesis, however, is currently under investigation. The aim of this comprehensive review is to first describe the background of hnRNP A1, including its structure, biological functions in RNA metabolism and the post-translational modifications known to modify its function. With this knowledge, the review then describes the influence of hnRNP A1 in neurodegenerative disease, and how its dysfunction may contribute the pathogenesis.

hnRNP A/B Proteins: An Encyclopedic Assessment of Their Roles in Homeostasis and Disease

“…In addition, A1 and A2/B1 have long been recognized as autoimmune targets, and recent work provides evidence that autoantibodies are not merely a by-product of autoimmune disease, but instead can pathologically impact A1 and A2/B1 function. For a specific and comprehensive review of A1 biology, we recommend Clarke et al [51], and for the same of A2/B1, we recommend Liu & Shi [52].…”

“…However, recent high-throughput work suggests that A2/B1 is biased towards binding activated exons [92] and 3'UTRs after splicing is complete [93]. Stimuli like hormone or growth factor signaling, acute stress induction, or innate immune activation and cytokine signaling, all result in reduced A1 RNA binding, permitting incorporation of alternative exons and retention of introns in the mRNA [51]. These stimuli likely also modulate A2/B1, although this has not been thoroughly explored.…”

“…Reduced RNA binding by A1 and A2/B1 results in either production of alternatively-spliced protein isoforms, or nonsense-mediated decay of mRNA with retained intronic sequences [46,91,[94][95][96][97][98]. Reduced RNA binding to facilitate alternative splicing appears to be mediated by posttranslational modifications of A1 such as phosphorylation or ubiquitination [51], but recent research also suggests that non-coding RNAs play a role in modulating the presence of A1 and A2/B1 at specific splicing suppressor and enhancer regions [99][100][101]. Given that noncoding RNAs direct A2/B1 in the context of transcription, it is likely that future research will find a role for them in regulating A2/B1 in splicing.…”

“…Upon delivery of their mRNA cargo to sites of translation or storage, A1 and A2/B1 return to the nucleus by a specific interaction with the nuclear import factor Transportin-1 (TNPO1, Karyopherinβ-2) [120,121] that requires RanGTP hydrolysis to release the hnRNP proteins back into the nucleus to repeat the cycle [122,123]. This process is heavily regulated by posttranslational modifications, where either O-GlcNAcylation [124] or SUMOylation [119] may mark cytoplasmic RNA-depleted A1 for return to the nucleus, while methylation, phosphorylation, acetylation, and PARylation may all prevent such a return [51]. Various stimuli, from growth factor and cytokine signaling to osmotic stressors and heat shock, drive these post-translational modifications and modulate A1 trafficking for rapid and short-term regulation of mRNA availability [51,125].…”

“…This process is heavily regulated by posttranslational modifications, where either O-GlcNAcylation [124] or SUMOylation [119] may mark cytoplasmic RNA-depleted A1 for return to the nucleus, while methylation, phosphorylation, acetylation, and PARylation may all prevent such a return [51]. Various stimuli, from growth factor and cytokine signaling to osmotic stressors and heat shock, drive these post-translational modifications and modulate A1 trafficking for rapid and short-term regulation of mRNA availability [51,125]. It currently appears that A2/B1 localization can be modulated by methylation [125][126][127], but future work will be required to clarify what regulates this for each isoform.…”