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Common genetic loci and pathological signatures have unified two seemingly different adult-onset neurodegenerative diseases, amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), which affect predominantly the motor system and cognition, respectively. In particular, mutations in TDP-43 are causal for both diseases coupled with the pathological TDP-43 inclusions present in the neurons and glia indicate that TDP-43 dysfunctions in these cells trigger ALS and FTD pathogenesis. Furthermore, TDP-43 aggregates, collectively known as TDP-43 proteinopathies, are common in aging human brains and in other neurodegenerative diseases, such as Alzheimer’s disease (AD),
underscoring the critical role of TDP-43 in brain health.
TDP-43 is ubiquitously expressed. Curiously, pathological TDP-43 also can be found in neurons, glia and other peripheral systems. Two key questions: the physiological functions of TDP-43 in different cell types, and whether the loss of TDP-43 in distinct glia contribute to ALS/FTD pathogenesis, remain unresolved. To this end, we systematically analyzed mice with TDP-43 deleted in distinct glia, including oligodendrocytes, Schwann cells and astrocytes. We uncovered that (1) TDP-43 is indispensable for oligodendrocyte survival and myelination by regulating SREBF2-mediated cholesterol metabolism, (2) TDP-43 is required for maximize conduction velocity by maintaining paranodal assembly in Schwann cells, and (3) TDP-43 maintains the protective status of astrocytes. Loss of TDP-43 function in each of the distinct glia results in motor deficits without apparent damage to motor neurons. These results highlight that TDP-43 participate in different physiological role in distinct glia, and TDP-43 dysfunction in different glia may be an integral part of ALS pathogenesis.