Altered localization and functionality of TAR DNA binding protein 43 (TDP-43) in niemann-pick disease type C

A. Dardis, S. Zampieri, S. Canterini, K. L. Newell, C. Stuani, J. R. Murrell, Bernardino Ghetti, M. T. Fiorenza, B. Bembi, E. Buratti

Research output: Contribution to journalArticle

6 Citations (Scopus)

Abstract

Niemann-Pick type C (NPC) disease is a lysosomal storage disorder characterized by the occurrence of visceral and neurological symptoms. At present, the molecular mechanisms causing neurodegeneration in this disease are unknown. Here we report the altered expression and/or mislocalization of the TAR-DNA binding protein 43 (TDP-43) in both NPC mouse and in a human neuronal model of the disease. We also report the neuropathologic study of a NPC patient's brain, showing that while TDP-43 is below immunohistochemical detection in nuclei of cerebellar Purkinje cells, it has a predominant localization in the cytoplasm of these cells. From a functional point of view, the TDP-43 mislocalization, that occurs in a human experimental neuronal model system, is associated with specific alterations in TDP-43 controlled genes. Most interestingly, treatment with N-Acetyl-cysteine (NAC) or beta-cyclodextrin (CD) can partially restore TDP-43 nuclear localization. Taken together, the results of these studies extend the role of TDP-43 beyond the Amyotrophic lateral sclerosis (ALS)/frontotemporal dementia (FTD)/Alzheimer disease (AD) spectrum. These findings may open novel research/therapeutic avenues for a better understanding of both NPC disease and the TDP-43 proteinopathy disease mechanism.

Original languageEnglish (US)
Article number52
JournalActa neuropathologica communications
Volume4
Issue number1
DOIs
StatePublished - 2016

Fingerprint

Type C Niemann-Pick Disease
DNA-Binding Proteins
Therapeutic Human Experimentation
Cerebellar Nuclei
Purkinje Cells
Cysteine
Alzheimer Disease
Cytoplasm
Theoretical Models
Brain

Keywords

  • Lysosomal diseases
  • Niemann Pick C
  • NPC1
  • TDP-43

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Dardis, A., Zampieri, S., Canterini, S., Newell, K. L., Stuani, C., Murrell, J. R., ... Buratti, E. (2016). Altered localization and functionality of TAR DNA binding protein 43 (TDP-43) in niemann-pick disease type C. Acta neuropathologica communications, 4(1), [52]. https://doi.org/10.1186/s40478-016-0325-4

Altered localization and functionality of TAR DNA binding protein 43 (TDP-43) in niemann-pick disease type C. / Dardis, A.; Zampieri, S.; Canterini, S.; Newell, K. L.; Stuani, C.; Murrell, J. R.; Ghetti, Bernardino; Fiorenza, M. T.; Bembi, B.; Buratti, E.

In: Acta neuropathologica communications, Vol. 4, No. 1, 52, 2016.

Research output: Contribution to journalArticle

Dardis, A, Zampieri, S, Canterini, S, Newell, KL, Stuani, C, Murrell, JR, Ghetti, B, Fiorenza, MT, Bembi, B & Buratti, E 2016, 'Altered localization and functionality of TAR DNA binding protein 43 (TDP-43) in niemann-pick disease type C', Acta neuropathologica communications, vol. 4, no. 1, 52. https://doi.org/10.1186/s40478-016-0325-4
Dardis, A. ; Zampieri, S. ; Canterini, S. ; Newell, K. L. ; Stuani, C. ; Murrell, J. R. ; Ghetti, Bernardino ; Fiorenza, M. T. ; Bembi, B. ; Buratti, E. / Altered localization and functionality of TAR DNA binding protein 43 (TDP-43) in niemann-pick disease type C. In: Acta neuropathologica communications. 2016 ; Vol. 4, No. 1.
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