baz-2 enhances systemic proteostasis in vivo by regulating acetylcholine metabolism.
Cell Rep
; 42(12): 113577, 2023 12 26.
Article
em En
| MEDLINE
| ID: mdl-38100354
ABSTRACT
Neurodegenerative disorders, such as Alzheimer's disease (AD) or Huntington's disease (HD), are linked to protein aggregate neurotoxicity. According to the "cholinergic hypothesis," loss of acetylcholine (ACh) signaling contributes to the AD pathology, and therapeutic restoration of ACh signaling is a common treatment strategy. How disease causation and the effect of ACh are linked to protein aggregation and neurotoxicity remains incompletely understood, thus limiting the development of more effective therapies. Here, we show that BAZ-2, the Caenorhabditis elegans ortholog of human BAZ2B, limits ACh signaling. baz-2 mutations reverse aggregation and toxicity of amyloid-beta as well as polyglutamine peptides, thereby restoring health and lifespan in nematode models of AD and HD, respectively. The neuroprotective effect of Δbaz-2 is mediated by choline acetyltransferase, phenocopied by ACh-esterase depletion, and dependent on ACh receptors. baz-2 reduction or ectopic ACh treatment augments proteostasis via induction of the endoplasmic reticulum unfolded protein response and the ubiquitin proteasome system.
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Base de dados:
MEDLINE
Assunto principal:
Doença de Huntington
/
Fatores Genéricos de Transcrição
/
Doença de Alzheimer
Idioma:
En
Ano de publicação:
2023
Tipo de documento:
Article