Heterogeneous Nuclear Ribonucleoprotein A1 and Its Impact on Multiple Sclerosis

Altered expression of the RNA binding protein heterogeneous nuclear ribonucleoprotein A1 (A1) is associated with reduced neuronal health and viability and may contribute to the pathogenesis of neurodegeneration in multiple sclerosis (MS), according to study results presented at the 2021 Annual Meeting of the Consortium of Multiple Sclerosis Centers (CMSC), held October 25 to 28, 2021 in Orlando, Florida.

Previous studies have shown that dysfunctional RNA-binding proteins may play an important role in the pathogenesis of neurodegeneration in neurologic disorders. Pathogenic features of an RNA-binding protein known as A1 were identified in neurons from patients with MS. The current study aimed at assessing the impact of reduced A1 nuclear expression on neuronal health and viability.

Neuro-2a cells and small interfering RNA to A1 were used to establish an in vitro model of decreased A1 neuronal expression. Western blotting was used to assess for cell death markers and cytotoxicity assays determined the effect of altered A1 nuclear expression on cell viability and cytotoxicity.

Neurons exposed to small interfering RNA to A1 showed significantly reduced A1 protein expression, compared with controls, with a significant reduction in neurite branching and neurite length (P <.0001). Reduced A1 may result in cell death through the necroptotic pathway, as cell death markers showed increased levels of phospho-mixed lineage kinase domain-like protein, a marker for necroptosis, but there was no change in active caspase-3 levels, a marker for apoptosis.

Decreased A1 nuclear expression was associated with increased cellular cytotoxicity, compared with controls (P =.04).

“Overall, this system models decreased A1 nuclear expression observed in MS brains and provides a relevant system to assess the consequences of A1 dysfunction on neuronal health and viability in the context of NDG [neurodegeneration],” concluded the researchers.

Reference

Anees A, Levin M, Salapa HE, Thibault P. Altered expression of the RNA binding protein heterogeneous nuclear ribonucleoprotein A1 (A1) contributes to the pathogenesis of neurodegeneration in multiple sclerosis. Presented atL CMSC 2021 Annual Meeting; October 25-28, 2021; Orlando, Florida. Abstract NPP02.