New insights of poly(ADP-ribosylation) in neurodegenerative diseases: A focus on protein phase separation and pathologic aggregation

Cong Liu; Yanshan Fang

doi:10.1016/j.bcp.2019.04.028

New insights of poly(ADP-ribosylation) in neurodegenerative diseases: A focus on protein phase separation and pathologic aggregation

Biochem Pharmacol. 2019 Sep:167:58-63. doi: 10.1016/j.bcp.2019.04.028. Epub 2019 Apr 26.

Authors

Cong Liu¹, Yanshan Fang²

Affiliations

¹ Interdisciplinary Research Center on Biology and Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai 201210, China; University of Chinese Academy of Sciences, Beijing 100049, China. Electronic address: liulab@sioc.ac.cn.
² Interdisciplinary Research Center on Biology and Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai 201210, China; University of Chinese Academy of Sciences, Beijing 100049, China. Electronic address: fangys@sioc.ac.cn.

PMID: 31034795
DOI: 10.1016/j.bcp.2019.04.028

Abstract

Abnormal protein aggregation is a common pathological feature of neurodegenerative diseases such as Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD) and amyotrophic lateral sclerosis (ALS). Protein posttranslational modifications (PTMs) play a crucial regulatory role in the formation of pathologic aggregation. Among the known PTMs involved in neurodegeneration, poly(ADP-ribosylation) (PARylation) has emerged with promising therapeutic potentials of the use of poly(ADP-ribose) (PAR) polymerase (PARP) inhibitors. In this review, we describe the mounting evidence that abnormal PARP activation is involved in various neurodegenerative diseases, and discuss the underpinning mechanisms with a focus on the recent findings that PARylation affects liquid-liquid phase separation and aggregation of amyloid proteins. We hope this review will stimulate further investigation of the unknown functions of PARylation and promote the development of more effective therapeutic agents in treating neurodegeneration.

Keywords: PARP; Phase separation; TDP-43; hnRNP A1; α-Synuclein.

Publication types

Research Support, Non-U.S. Gov't
Review

MeSH terms

Animals
DNA Damage / physiology
Humans
Neurodegenerative Diseases / drug therapy
Neurodegenerative Diseases / metabolism*
Neurodegenerative Diseases / pathology
Poly ADP Ribosylation / drug effects
Poly ADP Ribosylation / physiology*
Poly(ADP-ribose) Polymerase Inhibitors / pharmacology
Poly(ADP-ribose) Polymerase Inhibitors / therapeutic use*
Protein Aggregation, Pathological / drug therapy
Protein Aggregation, Pathological / metabolism*
Protein Aggregation, Pathological / pathology

Substances

Poly(ADP-ribose) Polymerase Inhibitors