SBT-272 improves TDP-43 pathology in ALS upper motor neurons by modulating mitochondrial integrity, motility, and function.
ATP
Cardiolipin
Electron transport chain
Motor neuron disease
Proteinopathy
SBT-272
TDP-43
Journal
Neurobiology of disease
ISSN: 1095-953X
Titre abrégé: Neurobiol Dis
Pays: United States
ID NLM: 9500169
Informations de publication
Date de publication:
03 2023
03 2023
Historique:
received:
23
09
2022
revised:
09
01
2023
accepted:
25
01
2023
pubmed:
31
1
2023
medline:
16
2
2023
entrez:
30
1
2023
Statut:
ppublish
Résumé
Mitochondrial defects are one of the common underlying causes of neuronal vulnerability in neurodegenerative diseases, such as amyotrophic lateral sclerosis (ALS), and TDP-43 pathology is the most commonly observed proteinopathy. Disrupted inner mitochondrial membrane (IMM) reported in the upper motor neurons (UMNs) of ALS patients with TDP-43 pathology is recapitulated in the UMNs of well-characterized hTDP-43 mouse model of ALS. The construct validity, such as shared and common cellular pathology in mice and human, offers a unique opportunity to test treatment strategies that may translate to patients. SBT-272 is a well-tolerated brain-penetrant small molecule that stabilizes cardiolipin, a phospholipid found in IMM, thereby restoring mitochondrial structure and respiratory function. We investigated whether SBT-272 can improve IMM structure and health in UMNs diseased with TDP-43 pathology in our well-characterized UMN reporter line for ALS. We found that SBT-272 significantly improved mitochondrial structural integrity and restored mitochondrial motility and function. This led to improved health of diseased UMNs in vitro. In comparison to edaravone and AMX0035, SBT-272 appeared more effective in restoring health of diseased UMNs. Chronic treatment of SBT-272 for sixty days starting at an early symptomatic stage of the disease in vivo led to a significant reduction in astrogliosis, microgliosis, and TDP-43 pathology in the ALS motor cortex. Our results underscore the therapeutic potential of SBT-272, especially within the context of TDP-43 pathology and mitochondrial dysfunction.
Identifiants
pubmed: 36716828
pii: S0969-9961(23)00036-0
doi: 10.1016/j.nbd.2023.106022
pii:
doi:
Substances chimiques
sodium phenylbutyrate and taurursodiol
0
DNA-Binding Proteins
0
TDP-43 protein, mouse
0
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
106022Subventions
Organisme : NINDS NIH HHS
ID : R21 NS085750
Pays : United States
Informations de copyright
Copyright © 2023. Published by Elsevier Inc.
Déclaration de conflit d'intérêts
Declaration of Competing Interest M.R. and H.Z. are paid employees with an equity stake in Stealth BioTherapeutics. D.K. is a past employee of Stealth Biotherapeutics. P.H.O. and Ozdinler laboratory members have no competing interests.