RNA-binding proteins as a common ground for neurodegeneration and inflammation in amyotrophic lateral sclerosis and multiple sclerosis

Abstract

The neurodegenerative and inflammatory illnesses of amyotrophic lateral sclerosis and multiple sclerosis were once thought to be completely distinct entities that did not share any remarkable features, but new research is beginning to reveal more information about their similarities and differences. Here, we review some of the pathophysiological features of both diseases and their experimental models: RNA-binding proteins, energy balance, protein transportation, and protein degradation at the molecular level. We make a thorough analysis on TDP-43 and hnRNP A1 dysfunction, as a possible common ground in both pathologies, establishing a potential link between neurodegeneration and pathological immunity. Furthermore, we highlight the putative variations that diverge from a common ground in an atemporal course that proposes three phases for all relevant molecular events.

Keywords: ALS; DNA-binding proteins; MS; RNA-binding proteins; TDP-43; autoimmunity; neurodegeneration.

Graphical abstract

The graphical abstract displays the common hallmarks between Amyotrophic Lateral Sclerosis and Multiple Sclerosis, as described in this review [adapted from Wilson et al. (2023)].

Figure 1

Principal pathophysiology mechanisms in amyotrophic lateral sclerosis (ALS). (A) RBP mislocalization by cellular stressors. (B) RBPs dysfunctionality: misfolding, and aggregation. (C) Mitochondrial dysfunction. (D) Proteostasis dysregulation. (E) Generation of stress granules. (F) Hyperexcitability. (G) Axonopathies. (H) Lysosome dysfunction and Autophagy Dysregulation. (I) Neuroinflammation.

Figure 2

Essential pathophysiology mechanisms in Multiple sclerosis (MS). (A) RBP mislocalization by cellular stressors. (B) RBPs dysfunctionality: misfolding, and aggregation. (C) Mitochondrial dysfunction. (D) Proteostasis dysregulation. (E) Generation of stress granules. (F) Hyperexcitability. (G) Axonopathies. (H) Neuroinflammation. (I) Plasma Cells. (J) Demyelination.

Figure 3

Proposed flow chart on the progress of ALS and MS. We describe three progressive phases that highlight the similarities and differences between ALS and MS. The first phase illustrates the principal known triggers of these diseases. The second phase highlights shared molecular hallmarks, and finally, the third phase represents imminent cellular death.