Metformin activates chaperone-mediated autophagy and improves disease pathologies in an Alzheimer disease mouse model

Xiaoyan Xu,Di Peng,Tingjun Hou,Qingwei Zhao,Xufeng Cen,Yaqin Sun,Tingxue Xie,Mengmeng Zhang,Hongguang Xia,Bing Shan,Cong Yi,Yu Xue,Zhe Wang,Ayaz Najafov,Qiming Sun

doi:10.1007/s13238-021-00858-3

Abstract

Chaperone-mediated autophagy (CMA) is a lysosome-dependent selective degradation pathway implicated in the pathogenesis of cancer and neurodegenerative diseases. However, the mechanisms that regulate CMA are not fully understood. Here, using unbiased drug screening approaches, we discover Metformin, a drug that is commonly the first medication prescribed for type 2 diabetes, can induce CMA. We delineate the mechanism of CMA induction by Metformin to be via activation of TAK1-IKKα/β signaling that leads to phosphorylation of Ser85 of the key mediator of CMA, Hsc70, and its activation. Notably, we find that amyloid-beta precursor protein (APP) is a CMA substrate and that it binds to Hsc70 in an IKKα/β-dependent manner. The inhibition of CMA-mediated degradation of APP enhances its cytotoxicity. Importantly, we find that in the APP/PS1 mouse model of Alzheimer’s disease (AD), activation of CMA by Hsc70 overexpression or Metformin potently reduces the accumulated brain Aβ plaque levels and reverses the molecular and behavioral AD phenotypes. Our study elucidates a novel mechanism of CMA regulation via Metformin-TAK1-IKKα/β-Hsc70 signaling and suggests Metformin as a new activator of CMA for diseases, such as AD, where such therapeutic intervention could be beneficial.

Highlights

Chaperone-mediated autophagy (CMA) is one of three types of autophagy and has been identified only in birds and mammals (Gough and Fambrough 1997)
Our study identifies Metformin as a novel CMA activator, sheds light on the mechanism of CMA activation by Metformin, and identifies amyloid-beta precursor protein (APP) as a novel CMA substrate, suggesting that Metformin-induced CMA activation and degradation of APP and Aβ can have beneficial effects in the context of pathogenesis of the Alzheimer’s disease
We identify the transforming growth factor betaactivated kinase1 (TAK1)-IKKα/β signaling to be the first regulatory input into the CMA pathway and show that IKKα/ β-mediated phosphorylation of Hsc70 at Ser85 controls its ability to interact with its substrates

Summary

Introduction

Chaperone-mediated autophagy (CMA) is one of three types of autophagy and has been identified only in birds and mammals (Gough and Fambrough 1997). The selectivity of CMA is due to the requirement for its substrates to contain the Lys-Phe-Glu-Arg-Gln (KFERQ) motif (Dice et al 1986; Dice 1990; Wing et al 1991). The CMA substrate proteins are recruited to the lysosomes by heat shock protein family A (Hsp70) member 8 (Hsc70), which recognizes the KFERQ motifs and delivers the substrates to the lysosomal membrane (Chiang et al 1989; Agarraberes and Dice 2001). Lysosomal associated membrane protein 2A (Lamp2a), a lysosomal receptor, mediates the translocation of CMA substrates into the lysosomal lumen, a process that is assisted by a luminal resident form of Hsc (Cuervo and Dice 1996; Agarraberes et al 1997). No protein kinase has yet been reported to directly phosphorylate and regulate Hsc activity

Methods

Results

Conclusion