Endo-lysosomal pathway and ubiquitin-proteasome system dysfunction in Alzheimer's disease pathogenesis

Jiqing Cao, Margaret B. Zhong, Carlos A. Toro, Larry Zhang, Dongming Cai

Research output: Contribution to journalReview articlepeer-review

51 Scopus citations

Abstract

Several lines of evidence have shown that defects in the endo-lysosomal autophagy degradation pathway and the ubiquitin-proteasome system play a role in Alzheimer's Disease (AD) pathogenesis and pathophysiology. Early pathological changes, such as marked enlargement of endosomal compartments, gradual accumulation of autophagic vacuoles (AVs) and lysosome dyshomeostasis, are well-recognized in AD. In addition to these pathological indicators, many genetic variants of key regulators in the endo-lysosomal autophagy networks and the ubiquitin-proteasome system have been found to be associated with AD. Furthermore, altered expression levels of key proteins in these pathways have been found in AD human brain tissues, primary cells and AD mouse models. In this review, we discuss potential disease mechanisms underlying the dysregulation of protein homeostasis governing systems. While the importance of two major protein degradation pathways in AD pathogenesis has been highlighted, targeted therapy at key components of these pathways has great potential in developing novel therapeutic interventions for AD. Future investigations are needed to define molecular mechanisms by which these complex regulatory systems become malfunctional at specific stages of AD development and progression, which will facilitate future development of novel therapeutic interventions. It is also critical to investigate all key components of the protein degradation pathways, both upstream and downstream, to improve our abilities to manipulate transport pathways with higher efficacy and less side effects.

Original languageEnglish (US)
Pages (from-to)68-78
Number of pages11
JournalNeuroscience Letters
Volume703
DOIs
StatePublished - Jun 11 2019
Externally publishedYes

Bibliographical note

Funding Information:
DC is supported by NIH R01 ( 1R01AG048923 ) and RF1 ( 1RF1AG054014 ), by Department of Veteran Affairs BLR&D ( 1I01BX003380 ) and RR&D ( 1I01RX002290 ), as well as by New York State SCI Foundation. JC is supported by NNSFC ( 81771162 ) and RF1 (1RF1AG054014 for DC). CAT is supported by New York State SCI Foundation. LZ is supported by NIH R01 (1R01AG048923 for DC) and RF1 (1RF1AG054014 for DC). We thank Dr. Jianwei Hou for his help in preparation of the figure.

Funding Information:
DC is supported by NIH R01 (1R01AG048923) and RF1 (1RF1AG054014), by Department of Veteran Affairs BLR&D (1I01BX003380) and RR&D (1I01RX002290), as well as by New York State SCI Foundation. JC is supported by NNSFC (81771162) and RF1 (1RF1AG054014 for DC). CAT is supported by New York State SCI Foundation. LZ is supported by NIH R01 (1R01AG048923 for DC) and RF1 (1RF1AG054014 for DC). We thank Dr. Jianwei Hou for his help in preparation of the figure.

Publisher Copyright:
© 2019

Keywords

  • Alzheimer's disease
  • Endo-lysosomal dysregulation
  • Impaired autophagy
  • Pathogenesis
  • Proteostasis
  • Ubiquitin-proteasome system

Fingerprint

Dive into the research topics of 'Endo-lysosomal pathway and ubiquitin-proteasome system dysfunction in Alzheimer's disease pathogenesis'. Together they form a unique fingerprint.

Cite this