Endocytosis regulates TDP-43 toxicity and turnover

Guangbo Liu, Alyssa N. Coyne, Fen Pei, Spencer Vaughan, Matthew Chaung, Daniela C Zarnescu, John R Buchan

Research output: Contribution to journalArticle

13 Citations (Scopus)

Abstract

Amyotrophic lateral sclerosis (ALS) is a fatal motor neuron degenerative disease. ALS-affected motor neurons exhibit aberrant localization of a nuclear RNA binding protein, TDP-43, into cytoplasmic aggregates, which contributes to pathology via unclear mechanisms. Here, we demonstrate that TDP-43 turnover and toxicity depend in part upon the endocytosis pathway. TDP-43 inhibits endocytosis, and co-localizes strongly with endocytic proteins, including in ALS patient tissue. Impairing endocytosis increases TDP-43 toxicity, aggregation, and protein levels, whereas enhancing endocytosis reverses these phenotypes. Locomotor dysfunction in a TDP-43 ALS fly model is also exacerbated and suppressed by impairment and enhancement of endocytic function, respectively. Thus, endocytosis dysfunction may be an underlying cause of ALS pathology.

Original languageEnglish (US)
Article number2092
JournalNature Communications
Volume8
Issue number1
DOIs
StatePublished - Dec 1 2017

Fingerprint

Amyotrophic Lateral Sclerosis
Pathology
Endocytosis
toxicity
Neurons
Toxicity
pathology
proteins
neurons
Nuclear RNA
RNA-Binding Proteins
Proteins
phenotype
Agglomeration
impairment
Tissue
Motor Neuron Disease
Motor Neurons
Nuclear Proteins
augmentation

ASJC Scopus subject areas

  • Chemistry(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Physics and Astronomy(all)

Cite this

Endocytosis regulates TDP-43 toxicity and turnover. / Liu, Guangbo; Coyne, Alyssa N.; Pei, Fen; Vaughan, Spencer; Chaung, Matthew; Zarnescu, Daniela C; Buchan, John R.

In: Nature Communications, Vol. 8, No. 1, 2092, 01.12.2017.

Research output: Contribution to journalArticle

Liu, Guangbo ; Coyne, Alyssa N. ; Pei, Fen ; Vaughan, Spencer ; Chaung, Matthew ; Zarnescu, Daniela C ; Buchan, John R. / Endocytosis regulates TDP-43 toxicity and turnover. In: Nature Communications. 2017 ; Vol. 8, No. 1.
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