baz-2 enhances systemic proteostasis in vivo by regulating acetylcholine metabolism
Christian Gallrein,
Ashley B. Williams,
David H. Meyer,
Jan-Erik Messling,
Antonio Garcia,
Björn Schumacher
Affiliations
Christian Gallrein
Institute for Genome Stability in Aging and Disease, Medical Faculty, University and University Hospital of Cologne, Joseph-Stelzmann-Strasse 26, 50931 Cologne, Germany; Cologne Excellence Cluster for Cellular Stress Responses in Aging-Associated Diseases (CECAD), Center for Molecular Medicine Cologne (CMMC), University of Cologne, Joseph-Stelzmann-Strasse 26, 50931 Cologne, Germany
Ashley B. Williams
Institute for Genome Stability in Aging and Disease, Medical Faculty, University and University Hospital of Cologne, Joseph-Stelzmann-Strasse 26, 50931 Cologne, Germany; Cologne Excellence Cluster for Cellular Stress Responses in Aging-Associated Diseases (CECAD), Center for Molecular Medicine Cologne (CMMC), University of Cologne, Joseph-Stelzmann-Strasse 26, 50931 Cologne, Germany
David H. Meyer
Institute for Genome Stability in Aging and Disease, Medical Faculty, University and University Hospital of Cologne, Joseph-Stelzmann-Strasse 26, 50931 Cologne, Germany; Cologne Excellence Cluster for Cellular Stress Responses in Aging-Associated Diseases (CECAD), Center for Molecular Medicine Cologne (CMMC), University of Cologne, Joseph-Stelzmann-Strasse 26, 50931 Cologne, Germany
Jan-Erik Messling
Institute for Genome Stability in Aging and Disease, Medical Faculty, University and University Hospital of Cologne, Joseph-Stelzmann-Strasse 26, 50931 Cologne, Germany
Antonio Garcia
Institute for Genome Stability in Aging and Disease, Medical Faculty, University and University Hospital of Cologne, Joseph-Stelzmann-Strasse 26, 50931 Cologne, Germany
Björn Schumacher
Institute for Genome Stability in Aging and Disease, Medical Faculty, University and University Hospital of Cologne, Joseph-Stelzmann-Strasse 26, 50931 Cologne, Germany; Cologne Excellence Cluster for Cellular Stress Responses in Aging-Associated Diseases (CECAD), Center for Molecular Medicine Cologne (CMMC), University of Cologne, Joseph-Stelzmann-Strasse 26, 50931 Cologne, Germany; Corresponding author
Summary: 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.
