Tfeb/mitf links impaired nuclear import to autophagolysosomal dysfunction in c9-als

Kathleen M. Cunningham, Kirstin Maulding, Kai Ruan, Mumine Senturk, Jonathan C. Grima, Hyun Sung, Zhongyuan Zuo, Helen Song, Junli Gao, Sandeep Dubey, Jeffrey D. Rothstein, Ke Zhang, Hugo J. Bellen, Thomas E. Lloyd

Research output: Contribution to journalArticlepeer-review

1 Scopus citations

Abstract

Disrupted nucleocytoplasmic transport (NCT) has been implicated in neurodegenerative disease pathogenesis; however, the mechanisms by which disrupted NCT causes neurodegeneration remain unclear. In a Drosophila screen, we identified ref(2)P/p62, a key regulator of autophagy, as a potent suppressor of neurodegeneration caused by the GGGGCC hexanucleotide repeat expansion (G4C2 HRE) in C9orf72 that causes amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). We found that p62 is increased and forms ubiquitinated aggregates due to decreased autophagic cargo degradation. Immunofluorescence and electron microscopy of Drosophila tissues demonstrate an accumulation of lysosome-like organelles that precedes neurodegeneration. These phenotypes are partially caused by cytoplasmic mislocalization of Mitf/TFEB, a key transcriptional regulator of autophagolysosomal function. Additionally, TFEB is mislocalized and downregulated in human cells expressing GGGGCC repeats and in C9-ALS patient motor cortex. Our data suggest that the C9orf72-HRE impairs Mitf/TFEB nuclear import, thereby disrupting autophagy and exacerbating proteostasis defects in C9-ALS/FTD.

Original languageEnglish (US)
Article numbere59419
Pages (from-to)1-35
Number of pages35
JournaleLife
Volume9
DOIs
StatePublished - Dec 2020

ASJC Scopus subject areas

  • Neuroscience(all)
  • Immunology and Microbiology(all)
  • Biochemistry, Genetics and Molecular Biology(all)

Fingerprint Dive into the research topics of 'Tfeb/mitf links impaired nuclear import to autophagolysosomal dysfunction in c9-als'. Together they form a unique fingerprint.

Cite this