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Brain. 2016 Mar;139(Pt 3):937-52. doi: 10.1093/brain/awv385. Epub 2016 Jan 19.

Improved proteostasis in the secretory pathway rescues Alzheimer's disease in the mouse.

Author information

1
1 Department of Medicine, University of Wisconsin-Madison, Madison, WI, USA.
2
2 Department of Cell and Molecular Pharmacology and Experimental Therapeutics, Medical University of South Carolina, Charleston, SC, USA.
3
1 Department of Medicine, University of Wisconsin-Madison, Madison, WI, USA 3 Neuroscience Training Program, University of Wisconsin-Madison, Madison, WI, USA.
4
4 Department of Neurology, University of Wisconsin-Madison, Madison, WI, USA.
5
3 Neuroscience Training Program, University of Wisconsin-Madison, Madison, WI, USA 4 Department of Neurology, University of Wisconsin-Madison, Madison, WI, USA.
6
2 Department of Cell and Molecular Pharmacology and Experimental Therapeutics, Medical University of South Carolina, Charleston, SC, USA lp1@medicine.wisc.edu pehar@musc.edu.
7
1 Department of Medicine, University of Wisconsin-Madison, Madison, WI, USA 3 Neuroscience Training Program, University of Wisconsin-Madison, Madison, WI, USA 5 Geriatric Research Education Clinical Center, VA Medical Center, Madison, WI, USA 6 Department of Neuroscience, University of Wisconsin-Madison, Madison, WI, USA 7 Wisconsin Alzheimer's Disease Research Center, University of Wisconsin-Madison, Madison, WI, USA lp1@medicine.wisc.edu pehar@musc.edu.

Abstract

The aberrant accumulation of toxic protein aggregates is a key feature of many neurodegenerative diseases, including Huntington's disease, amyotrophic lateral sclerosis and Alzheimer's disease. As such, improving normal proteostatic mechanisms is an active target for biomedical research. Although they share common pathological features, protein aggregates form in different subcellular locations. Nε-lysine acetylation in the lumen of the endoplasmic reticulum has recently emerged as a new mechanism to regulate the induction of autophagy. The endoplasmic reticulum acetylation machinery includes AT-1/SLC33A1, a membrane transporter that translocates acetyl-CoA from the cytosol into the endoplasmic reticulum lumen, and ATase1 and ATase2, two acetyltransferases that acetylate endoplasmic reticulum cargo proteins. Here, we used a mutant form of α-synuclein to show that inhibition of the endoplasmic reticulum acetylation machinery specifically improves autophagy-mediated disposal of toxic protein aggregates that form within the secretory pathway, but not those that form in the cytosol. Consequently, haploinsufficiency of AT-1/SLC33A1 in the mouse rescued Alzheimer's disease, but not Huntington's disease or amyotrophic lateral sclerosis. In fact, intracellular toxic protein aggregates in Alzheimer's disease form within the secretory pathway while in Huntington's disease and amyotrophic lateral sclerosis they form in different cellular compartments. Furthermore, biochemical inhibition of ATase1 and ATase2 was also able to rescue the Alzheimer's disease phenotype in a mouse model of the disease. Specifically, we observed reduced levels of soluble amyloid-β aggregates, reduced amyloid-β pathology, reduced phosphorylation of tau, improved synaptic plasticity, and increased lifespan of the animals. In conclusion, our results indicate that Nε-lysine acetylation in the endoplasmic reticulum lumen regulates normal proteostasis of the secretory pathway; they also support therapies targeting endoplasmic reticulum acetyltransferases, ATase1 and ATase2, for a subset of chronic degenerative diseases.

KEYWORDS:

AT-1/SLC33A1; ATase; Alzheimer’s disease; autophagy; lysine acetylation; proteostasis

PMID:
26787453
PMCID:
PMC4805081
[Available on 2017-03-01]
DOI:
10.1093/brain/awv385
[Indexed for MEDLINE]
Free PMC Article

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