TDP-43 proteinopathy occurs independently of autophagic substrate accumulation and underlies nuclear defects in Niemann-Pick C disease

Neuropathol Appl Neurobiol. 2021 Dec;47(7):1019-1032. doi: 10.1111/nan.12738. Epub 2021 Jun 15.


Aims: Neuronal cytoplasmic inclusions of TAR-DNA binding protein of 43 kDa (TDP-43) are a pathological hallmark of diverse neurodegenerative disorders, yet the processes that mediate their formation and their functional significance remain incompletely understood. Both dysfunction in autophagy and neuroinflammation have been linked to TDP-43 mislocalisation. Here, we investigate TDP-43 proteinopathy in Niemann-Pick type C disease (NPC), an autosomal recessive lysosomal storage disease (LSD) distinguished by the accumulation of unesterified cholesterol within late endosomes and lysosomes. NPC is characterised by neurodegeneration, neuroinflammation and multifocal disruption of the autophagy pathway.

Methods: We utilised immunohistochemistry, confocal microscopy, electron microscopy and biochemical and gene expression studies to characterise TDP-43 pathology and autophagic substrate accumulation in Npc1-deficient mice.

Results: In the NPC brain, cytoplasmic TDP-43 mislocalisation was independent of autophagic substrate accumulation. These pathologies occurred in distinct neuronal subtypes, as brainstem cholinergic neurons were more susceptible to TDP-43 mislocalisation, whereas glutamatergic neurons exhibited hallmarks of autophagic dysfunction. Furthermore, TDP-43 mislocalisation did not co-localise with markers of stress granules or progress to ubiquitinated aggregates over months in vivo, indicating a stable, early stage in the aggregation process. Neither microgliosis nor neuroinflammation were sufficient to drive TDP-43 proteinopathy in the NPC brain. Notably, cytoplasmic TDP-43 co-localised with the nuclear import factor importin α, and TDP-43 mislocalised neurons demonstrated nuclear membrane abnormalities and disruption of nucleocytoplasmic transport.

Conclusion: Our findings highlight the relationship between LSDs and TDP-43 proteinopathy, define its functional importance in NPC by triggering nuclear dysfunction, and expand the spectrum of TDP-43 pathology in the diseased brain.

Keywords: Niemann-Pick type C; TDP-43; autophagy; lysosomal diseases; nucleocytoplasmic transport.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Autophagy / genetics*
  • Brain / pathology
  • DNA-Binding Proteins / genetics
  • DNA-Binding Proteins / metabolism*
  • Intracellular Signaling Peptides and Proteins / metabolism
  • Lysosomes / metabolism
  • Mice
  • Neuroinflammatory Diseases / genetics
  • Neuroinflammatory Diseases / metabolism
  • Neuroinflammatory Diseases / pathology
  • Neurons / pathology
  • Niemann-Pick Disease, Type C / genetics*
  • Niemann-Pick Disease, Type C / metabolism
  • Niemann-Pick Disease, Type C / pathology*
  • TDP-43 Proteinopathies / genetics
  • TDP-43 Proteinopathies / metabolism


  • DNA-Binding Proteins
  • Intracellular Signaling Peptides and Proteins
  • TDP-43 protein, mouse