Stage-specific control of oligodendrocyte survival and morphogenesis by TDP-43

Abstract

Generation of oligodendrocytes in the adult brain enables both adaptive changes in neural circuits and regeneration of myelin sheaths destroyed by injury, disease, and normal aging. This transformation of oligodendrocyte precursor cells (OPCs) into myelinating oligodendrocytes requires processing of distinct mRNAs at different stages of cell maturation. Although mislocalization and aggregation of the RNA-binding protein, TDP-43, occur in both neurons and glia in neurodegenerative diseases, the consequences of TDP-43 loss within different stages of the oligodendrocyte lineage are not well understood. By performing stage-specific genetic inactivation of Tardbp in vivo, we show that oligodendrocyte lineage cells are differentially sensitive to loss of TDP-43. While OPCs depend on TDP-43 for survival, with conditional deletion resulting in cascading cell loss followed by rapid regeneration to restore their density, oligodendrocytes become less sensitive to TDP-43 depletion as they mature. Deletion of TDP-43 early in the maturation process led to eventual oligodendrocyte degeneration, seizures, and premature lethality, while oligodendrocytes that experienced late deletion survived and mice exhibited a normal lifespan. At both stages, TDP-43-deficient oligodendrocytes formed fewer and thinner myelin sheaths and extended new processes that inappropriately wrapped neuronal somata and blood vessels. Transcriptional analysis revealed that in the absence of TDP-43, key proteins involved in oligodendrocyte maturation and myelination were misspliced, leading to aberrant incorporation of cryptic exons. Inducible deletion of TDP-43 from oligodendrocytes in the adult central nervous system (CNS) induced the same progressive morphological changes and mice acquired profound hindlimb weakness, suggesting that loss of TDP-43 function in oligodendrocytes may contribute to neuronal dysfunction in neurodegenerative disease.

TDP-43 dysregulation and neuromuscular junction disruption in amyotrophic lateral sclerosis

“…In contrast, astrocyte-specific TDP-43 depletion in mice does not cause NMJ denervation or MN loss, but induces an A1-like reactive astrocyte molecular profile, upregulation of C1 complement expression in microglia (a marker of reactive microglia), and reduces the number of mature oligodendrocytes, referred by the authors as “triglial dysfunction” [ 255 ]. Similarly, selective depletion of TDP-43 in oligodendrocytes is insufficient to cause NMJ denervation or MN loss, but it is essential for oligodendrocyte survival and myelination [ 256 – 258 ].…”

TDP-43 and other hnRNPs regulate cryptic exon inclusion of a key ALS/FTD risk gene, UNC13A

“…Indeed, several hnRNPs can bind the RNA targets of TDP-43 and regulate their splicing [17,40,46], and RNA levels of certain hnRNPs are elevated in FTLD-TDP [17]. TDP-43's role in the repression of cryptic exons had been shown to be cell-type specific, with unique targets identified in neurons, stems cells, muscle cells, Schwann cells, and oligodendrocytes [8,12,[47][48][49]. Susnjar and colleagues have proposed differential expression of RBPs in cells and tissue may mediate the variability of TDP-43 targets [50].…”

pTDP-43 levels correlate with cell type specific molecular alterations in the prefrontal cortex ofC9orf72ALS/FTD patients

“…These findings further strengthen our suggestion that a large portion of oligodendrocytes in the dorsolateral prefrontal cortex in late FTD disease stages are defective in myelination. mRNAs encoded by these genes are bound by pTDP-43 in the mouse brain 27,28 and the development of oligodendrocytes has been shown to be regulated by TDP-43 29 . Given prior evidence of pTDP-43 inclusions in oligodendrocytes, we speculate that pTDP-43 aggregates may play a direct role in dysregulating mRNAs encoding myelin components, thus affecting the maturation of oligodendrocytes and their ability to myelinate neurons, a unique feature to C9orf72 ALS/FTD patients with significant pTDP-43 burden.…”

“…Our data demonstrate that cases with high pTDP-43 burden contain a high proportion of newly differentiated/pre-mature oligodendrocytes (ODC-C6). The relatively low expression of genes encoding myelin protein components in this cell cluster may be due to high cytoplasmic pTDP-43 accumulation, since this protein is involved in the posttranscriptional regulation of myelin proteins 27,29 . We do not observe a significant change in oligodendrocyte progenitor cells, suggesting that the cluster of premature oligodendrocytes is likely a result of its inability to become mature due to the downregulation of myelin components.…”