Cell-autonomous requirement of TDP-43, an ALS/FTD signature protein, for oligodendrocyte survival and myelination

Abstract

TDP-43 aggregates in neurons and glia are the defining pathological hallmark of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), raising the possibility of glial damage in the disease pathogenesis. However, the normal physiological functions of TDP-43 in glia are largely unknown. To address how TDP-43 may be required for oligodendroglial functions we selectively deleted TDP-43 in mature oligodendrocytes in mice. Although mice with TDP-43 deleted in oligodendrocytes are born in an expected Mendelian ratio, they develop progressive neurological phenotypes leading to early lethality accompanied by a progressive reduction in myelination. The progressive myelin reduction is likely due to a combination of the cell-autonomous RIPK1-mediated necroptosis of mature oligodendrocytes and the TDP-43–dependent reduction in the expression of myelin genes. Strikingly, enhanced proliferation of NG2-positive oligodendrocyte precursor cells within the white matter, but not the gray matter, was able to replenish the loss of mature oligodendrocytes, indicating an intrinsic regeneration difference between the gray and white matter oligodendrocytes. By contrast, there was no loss of spinal cord motor neurons and no sign of denervation at the neuromuscular synapses. Taken together, our data demonstrate that TDP-43 is indispensable for oligodendrocyte survival and myelination, and loss of TDP-43 in oligodendrocytes exerts no apparent toxicity on motor neurons.

RNA-binding protein altered expression and mislocalization in multiple sclerosis

“…Importantly and relevant to our findings is a recent report that an experimental decrease in expression of TDP-43 in mature oligodendrocytes in mice leads to demyelination and RIPK1-mediated necroptosis of oligodendrocytes 6 ; of note, necroptosis has been reported to occur in MS as well as experimental models of MS 25 . A conclusion of that investigation was that the TDP-43 knockdown led to a reduction in myelin gene expression, and that TDP-43 is indispensable for oligodendrocyte survival and demyelination 6 . These findings suggest that nuclear depletion and mislocalization of TDP-43 in MS lesions would similarly lead to demyelination and, in some cases, death of oligodendrocytes.…”

“…These results suggest that altered expression of RBPs in demyelinating lesions of MS may disrupt key cellular processes, and thereby contribute to the pathogenesis of demyelination and neurodegeneration. A recent publication demonstrated that TDP-43 is important for oligodendrocyte survival and myelination 6 . In addition, PTB is known to be critically important for splicing repression and neuronal differentiation 7,8 .…”

RNA-binding protein altered expression and mislocalization in MS

“…4 Because TMEV-induced demyelinating disease serves as an experimental model of MS, we next examined the expression pattern and localization of these RBPs in MS. We now report nuclear depletion and mislocalization of TDP-43 and PTB in MS lesions and in vitro cultured oligodendrocytes. Recent publications stress the importance of TDP-43 for oligodendrocyte survival and myelination, 5 and of PTB for neuronal differentiation, 6,7 suggesting a role for these RBPs in MS pathogenesis and the potential importance of nucleocytoplasmic transport as a target for treatment.…”

Dysfunctional RNA‐binding protein biology and neurodegeneration in experimental autoimmune encephalomyelitis in female mice

“…However, CD68, the marker used in this study, is a classical macrophage marker that does not discriminate between subpopulations of macrophages, such as the aforementioned proand anti-inflammatory subtypes (Barros, Hauck, Dreyer, Kempkes, & Niedobitek, 2013). Although we found a relationship between T cells and hnRNP A1 mislocalization, it did not account for all of the (Masaki et al, 2019;Wang et al, 2018). Previous studies using MOG-induced EAE showed no sex differences in disease incidence, clinical score, histology of the central nervous system, MOG antibodies, T cell responses, or cytokine production of immune cells (Okuda, Okuda, & Bernard, 2002;Papenfuss et al, 2004).…”

“…RBP mislocalization is influenced by a number of factors, including cytokines, osmotic stress, and ER stress (Colombrita et al, 2009;Correia et al, 2015;Liu-Yesucevitz et al, 2010;Salapa et al, 2018;Walker et al, 2013). However, CD68, the marker used in this study, is a classical macrophage marker that does not discriminate between subpopulations of macrophages, such as the aforementioned proand anti-inflammatory subtypes (Barros, Hauck, Dreyer, Kempkes, & Niedobitek, 2013 (Masaki et al, 2019;Wang et al, 2018). T cells are potent producers of IFNγ.…”