SBT-272 improves TDP-43 pathology in ALS upper motor neurons by modulating mitochondrial integrity, motility, and function

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 mot...

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Published in:Neurobiology of disease Vol. 178; p. 106022
Main Authors: Gautam, Mukesh, Genç, Barış, Helmold, Benjamin, Ahrens, Angela, Kuka, Janis, Makrecka-Kuka, Marina, Günay, Aksu, Koçak, Nuran, Aguilar-Wickings, Izaak R., Keefe, Dennis, Zheng, Guozhu, Swaminathan, Suchitra, Redmon, Martin, Zariwala, Hatim A., Özdinler, P. Hande
Format: Journal Article
Language:English
Published: United States Elsevier Inc 01.03.2023
Elsevier
Subjects:
Amyotrophic Lateral Sclerosis - metabolism
Animals
ATP
Cardiolipin
DNA-Binding Proteins - metabolism
Electron transport chain
Humans
Mice
Mitochondria - pathology
Motor neuron disease
Motor Neurons - pathology
Proteinopathy
SBT-272
TDP-43
Proteinopathy
VCP
IHC
Motor neuron disease
ALS
OXPHOS
PFA
TMPD
ADP
CTIP2
CLEM
CSMN
Electron transport chain
mSOD1
BSA
UCHL1
CHCHD3
ANOVA
SFM
SBT-272
eGFP
GI
P3
FTLD
EM
IMM
CL
OMM
DIV
ET-1
TDP-43
ROS
UMN
ROX
Cardiolipin
ATP
ISSN:0969-9961, 1095-953X, 1095-953X
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Summary: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. •Early and progressive upper motor neuron (UMN) degeneration defines ALS pathology•Mitochondrial defects are prominent and common in UMNs with TDP-43 pathology•SBT-272 treatment improves mitochondrial stability, mobility and function•SBT-272 treatment reduces astrogliosis, microgliosis and TDP-43 pathology
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ISSN:0969-9961
1095-953X
1095-953X
DOI:10.1016/j.nbd.2023.106022