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Gautam 2023 Neurobiol Dis

From Bioblast
Publications in the MiPMap
Gautam M, Genç B, Helmold B, Ahrens A, Kuka J, Makrecka-Kuka M, Günay A, Koçak N, Aguilar-Wickings IR, Keefe D, Zheng G, Swaminathan S, Redmon M, Zariwala HA, Özdinler PH (2023) SBT-272 improves TDP-43 pathology in ALS upper motor neurons by modulating mitochondrial integrity, motility, and function.

» Neurobiol Dis 178:106022. PMID: 36716828 Open Access

Gautam Mukesh, Genc Baris, Helmold Benjamin, Ahrens Angela, Kuka Janis, Makrecka-Kuka Marina, Guenay Aksu, Kocak Nuran, Aguilar-Wickings Izaak R, Keefe Dennis, Zheng Guozhu, Swaminathan Suchitra, Redmon Martin, Zariwala Hatim A, Oezdinler P Hande (2023) Neurobiol Dis

Abstract: Mitochondrial defects are one of the common underlying causes of neuronal vulnerability in motor neuron diseases, such as amyotrophic lateral sclerosis (ALS), and TDP-43 pathology is the most common proteinopathy in ALS. 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 mutant hTDP-43 mouse model of ALS. The construct validity, such as common cellular pathology in mice and human, offers a unique opportunity to test treatment strategies that may translate. 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. Keywords: ATP, Cardiolipin, Electron transport chain, Motor neuron disease, Proteinopathy, SBT-272, TDP-43 Bioblast editor: Plangger M

On terminology

» Mitochondrial states and rates - terminology beyond MitoEAGLE 2020
For harmonization of terminology on respiratory states and rates, see


MitoEAGLE terminology 

Labels: MiParea: Respiration, Pharmacology;toxicology  Pathology: Neurodegenerative 

Organism: Rat  Tissue;cell: Heart, Nervous system  Preparation: Permeabilized tissue, Homogenate 

Coupling state: LEAK, OXPHOS  Pathway: N, S, CIV, NS, ROX  HRR: Oxygraph-2k, O2k-Fluorometer 

2023-01, AmR