C9orf72 ALS/FTD dipeptide repeat protein levels are reduced by small molecules that inhibit PKA or enhance protein degradation.
Animals
C9orf72 Protein
/ metabolism
Cell Line
Codon, Initiator
/ genetics
Cyclic AMP-Dependent Protein Kinases
/ antagonists & inhibitors
DNA Repeat Expansion
/ genetics
Dipeptides
/ metabolism
Disease Models, Animal
Drosophila
/ drug effects
Frontotemporal Dementia
/ pathology
HEK293 Cells
High-Throughput Screening Assays
Humans
Induced Pluripotent Stem Cells
/ pathology
Isoquinolines
/ pharmacology
Longevity
/ drug effects
Motor Neurons
/ drug effects
Protein Biosynthesis
/ drug effects
Proteolysis
/ drug effects
RNA Interference
Small Molecule Libraries
/ pharmacology
Sulfonamides
/ pharmacology
C9orf72
C9ALS/FTD
DPR
PKA
protein clearance
Journal
The EMBO journal
ISSN: 1460-2075
Titre abrégé: EMBO J
Pays: England
ID NLM: 8208664
Informations de publication
Date de publication:
04 01 2022
04 01 2022
Historique:
revised:
21
09
2021
received:
17
03
2020
accepted:
12
10
2021
pubmed:
19
11
2021
medline:
13
1
2022
entrez:
18
11
2021
Statut:
ppublish
Résumé
Intronic GGGGCC (G4C2) hexanucleotide repeat expansion within the human C9orf72 gene represents the most common cause of familial forms of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) (C9ALS/FTD). Repeat-associated non-AUG (RAN) translation of repeat-containing C9orf72 RNA results in the production of neurotoxic dipeptide-repeat proteins (DPRs). Here, we developed a high-throughput drug screen for the identification of positive and negative modulators of DPR levels. We found that HSP90 inhibitor geldanamycin and aldosterone antagonist spironolactone reduced DPR levels by promoting protein degradation via the proteasome and autophagy pathways respectively. Surprisingly, cAMP-elevating compounds boosting protein kinase A (PKA) activity increased DPR levels. Inhibition of PKA activity, by both pharmacological and genetic approaches, reduced DPR levels in cells and rescued pathological phenotypes in a Drosophila model of C9ALS/FTD. Moreover, knockdown of PKA-catalytic subunits correlated with reduced translation efficiency of DPRs, while the PKA inhibitor H89 reduced endogenous DPR levels in C9ALS/FTD patient-derived iPSC motor neurons. Together, our results suggest new and druggable pathways modulating DPR levels in C9ALS/FTD.
Identifiants
pubmed: 34791698
doi: 10.15252/embj.2020105026
pmc: PMC8724771
doi:
Substances chimiques
C9orf72 Protein
0
Codon, Initiator
0
Dipeptides
0
Isoquinolines
0
Small Molecule Libraries
0
Sulfonamides
0
Cyclic AMP-Dependent Protein Kinases
EC 2.7.11.11
N-(2-(4-bromocinnamylamino)ethyl)-5-isoquinolinesulfonamide
M876330O56
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
e105026Subventions
Organisme : Medical Research Council
Pays : United Kingdom
Informations de copyright
© 2021 The Authors Published under the terms of the CC BY NC ND 4.0 license.
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