Ubiquitin signalling in neurodegeneration: mechanisms and therapeutic opportunities.
Amyloid beta-Peptides
/ metabolism
Animals
Autophagy
/ physiology
Cell Death
Humans
Lysosomes
/ physiology
Mitochondria
/ metabolism
Neurodegenerative Diseases
/ metabolism
Proteasome Endopeptidase Complex
/ metabolism
Signal Transduction
Ubiquitin
/ metabolism
alpha-Synuclein
/ metabolism
tau Proteins
/ metabolism
Journal
Cell death and differentiation
ISSN: 1476-5403
Titre abrégé: Cell Death Differ
Pays: England
ID NLM: 9437445
Informations de publication
Date de publication:
02 2021
02 2021
Historique:
received:
15
11
2020
accepted:
01
12
2020
revised:
01
12
2020
pubmed:
9
1
2021
medline:
16
12
2021
entrez:
8
1
2021
Statut:
ppublish
Résumé
Neurodegenerative diseases are characterised by progressive damage to the nervous system including the selective loss of vulnerable populations of neurons leading to motor symptoms and cognitive decline. Despite millions of people being affected worldwide, there are still no drugs that block the neurodegenerative process to stop or slow disease progression. Neuronal death in these diseases is often linked to the misfolded proteins that aggregate within the brain (proteinopathies) as a result of disease-related gene mutations or abnormal protein homoeostasis. There are two major degradation pathways to rid a cell of unwanted or misfolded proteins to prevent their accumulation and to maintain the health of a cell: the ubiquitin-proteasome system and the autophagy-lysosomal pathway. Both of these degradative pathways depend on the modification of targets with ubiquitin. Aging is the primary risk factor of most neurodegenerative diseases including Alzheimer's disease, Parkinson's disease and amyotrophic lateral sclerosis. With aging there is a general reduction in proteasomal degradation and autophagy, and a consequent increase of potentially neurotoxic protein aggregates of β-amyloid, tau, α-synuclein, SOD1 and TDP-43. An often over-looked yet major component of these aggregates is ubiquitin, implicating these protein aggregates as either an adaptive response to toxic misfolded proteins or as evidence of dysregulated ubiquitin-mediated degradation driving toxic aggregation. In addition, non-degradative ubiquitin signalling is critical for homoeostatic mechanisms fundamental for neuronal function and survival, including mitochondrial homoeostasis, receptor trafficking and DNA damage responses, whilst also playing a role in inflammatory processes. This review will discuss the current understanding of the role of ubiquitin-dependent processes in the progressive loss of neurons and the emergence of ubiquitin signalling as a target for the development of much needed new drugs to treat neurodegenerative disease.
Identifiants
pubmed: 33414510
doi: 10.1038/s41418-020-00706-7
pii: 10.1038/s41418-020-00706-7
pmc: PMC7862249
doi:
Substances chimiques
Amyloid beta-Peptides
0
Ubiquitin
0
alpha-Synuclein
0
tau Proteins
0
Proteasome Endopeptidase Complex
EC 3.4.25.1
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Review
Langues
eng
Sous-ensembles de citation
IM
Pagination
570-590Références
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