Impaired ERAD and ER stress are early and specific events in polyglutamine toxicity.
Protein misfolding, whether caused by aging, environmental factors, or genetic mutations, is a common basis for neurodegenerative diseases. The misfolding of proteins with abnormally long polyglutamine (polyQ) expansions causes several neurodegenerative disorders, such as Huntington's disease (HD). Although many cellular pathways have been documented to be impaired in HD, the primary triggers of polyQ toxicity remain elusive. We report that yeast cells and neuron-like PC12 cells expressing polyQ-expanded huntingtin (htt) fragments display a surprisingly specific, immediate, and drastic defect in endoplasmic reticulum (ER)-associated degradation (ERAD). We further decipher the mechanistic basis for this defect in ERAD: the entrapment of the essential ERAD proteins Npl4, Ufd1, and p97 by polyQ-expanded htt fragments. In both yeast and mammalian neuron-like cells, overexpression of Npl4 and Ufd1 ameliorates polyQ toxicity. Our results establish that impaired ER protein homeostasis is a broad and highly conserved contributor to polyQ toxicity in yeast, in PC12 cells, and, importantly, in striatal cells expressing full-length polyQ-expanded huntingtin.
Duennwald
Martin L
ML
The Whitehead Institute for Biomedical Research, Cambridge, Massachusetts 02142, USA.
Lindquist
Susan
S
D000818:Animals; D003342:Corpus Striatum / Q000378:metabolism; D004721:Endoplasmic Reticulum / Q000187:drug effects*; D018869:Heat-Shock Response; D006706:Homeostasis; D000071058:Huntingtin Protein; D009154:Mutation; D009419:Nerve Tissue Proteins / Q000378:metabolism; D009687:Nuclear Proteins / Q000378:metabolism; D016716:PC12 Cells; D010446:Peptide Fragments / Q000378:metabolism; D010455:Peptides / Q000633:toxicity*; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D017510:Protein Folding; D051381:Rats; D012441:Saccharomyces cerevisiae; D029701:Saccharomyces cerevisiae Proteins / Q000378:metabolism; D015398:Signal Transduction; D025801:Ubiquitin / Q000378:metabolism; D033921:Vesicular Transport Proteins
C499524:Htt protein, rat; D000071058:Huntingtin Protein; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; D010446:Peptide Fragments; D010455:Peptides; D029701:Saccharomyces cerevisiae Proteins; C444652:UFD1 protein, S cerevisiae; D025801:Ubiquitin; D033921:Vesicular Transport Proteins; C097188:polyglutamine; D046988:Proteasome Endopeptidase Complex