Contribution of RNA/DNA Binding Protein Dysfunction in Oligodendrocytes in the Pathogenesis of the Amyotrophic Lateral Sclerosis/Frontotemporal Lobar Degeneration Spectrum Diseases

Abstract

Amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD) are two incurable neurodegenerative disorders, often considered as the extreme manifestations of a disease spectrum, as they share similar pathomechanisms. In support of this, pathological aggregation of the RNA/DNA binding proteins trans-activation response element DNA-binding protein 43 (TDP-43) or fused in sarcoma (FUS) is the pathological hallmark found in neurons and glial cells of subsets of patients affected by either condition (i.e., ALS/FTLD-TDP-43 or ALS/FTLD-FUS, respectively). Among glia, oligodendrocytes are the most abundant population, designated to ensheath the axons with myelin and to provide them with metabolic and trophic support. In this minireview, we recapitulate the neuropathological evidence for oligodendroglia impairment in ALS/FTLD. We then debate how TDP-43 and FUS target oligodendrocyte transcripts, thereby controlling their homeostatic abilities toward the axons. Finally, we discuss cellular and animal models aimed at investigating the functional consequences of manipulating TDP-43 and FUS in oligodendrocytes in vivo. Taken together, current data provide increasing evidence for an important role of TDP-43 and FUS-mediated oligodendroglia dysfunction in the pathogenesis of ALS/FTLD. Thus, targeting disrupted oligodendroglial functions may represent a new treatment approach for these conditions.

Keywords: ALS; FTLD; FUS; TDP-43; oligodendrocytes.

FIGURE 1

Oligodendroglial pathology in TDP-43 and FUS proteinopathies. (A) Glial cytoplasmic inclusions (GCI) are a characteristic feature with presence in variable amounts in affected brain regions in ALS—TDP, in subtypes of FTLD—TDP (particularly types B, E), subtypes of ALS—FUS (particularly in pattern 1 associated with adult onset and longer disease duration), and all distinct entities of FTLD—FUS, including aFTLD-U, basophilic inclusion body disease, and neuronal intermediate filament inclusion disease. Semiquantitative scores: 0, absent;+, rare;++, moderate; +++, abundant. (B–E) Immunohistochemistry of human postmortem tissues with pTDP-43 S409/410 antibody (Neumann et al., 2009a) demonstrating numerous GCI (arrowheads) in spinal cord of ALS—TDP case (B) and frontal cortex of FTLD—TDP type B case (C), and FUS (Proteintech) immunohistochemistry demonstrating GCI in spinal cord of ALS-FUS case with pattern 1 pathology (D) and basal ganglia of FTLD—FUS (basophilic inclusion body disease) case (E) in addition to neuronal cytoplasmic inclusions (arrow). Scale bar in panel B = 20 μm.

FIGURE 2

Schematic of potential mechanisms of oligodendrocyte dysfunction in pathogenesis of TDP-43/FUS proteinopathies. TDP-43 and FUS pathology in oligodendrocytes might modulate oligodendrocyte biology by binding to several transcripts (1a) and regulating pre-mRNA splicing (1b). Furthermore, it might affect transport of key RNA transcripts such as Mbp (2) and perturb bidirectional communication with axons (3). Created with BioRender.com.