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

Gautam, M.; Genc, B.; Helmold, B.; Ahrens, A.; Kuka, J.; Makrecka-Kuka, M.; Gunay, A.; Kocak, N.; Aguilar-Wickings, I. R.; Keefe, D.; Zheng, G.; Swaminathan, S.; Redmon, M.; Zariwala, H. A.; Ozdinler, P. H.

doi:10.1101/2022.10.04.510854

bioRxiv · 10.1101/2022.10.04.510854

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

Gautam, M.·Genc, B.·Helmold, B.·Ahrens, A.·Kuka, J.·Makrecka-Kuka, M.·Gunay, A.·Kocak, N.·Aguilar-Wickings, I. R.·Keefe, D.·Zheng, G.·Swaminathan, S.·Redmon, M.·Zariwala, H. A.·Ozdinler, P. H.

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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 models 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 reduction in astrogliosis, microgliosis, and retention of UMN degeneration 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. HighlightsO_LIEarly and progressive upper motor neuron (UMN) degeneration defines ALS pathology C_LIO_LIMitochondrial defects are prominent and common in UMNs with TDP-43 pathology C_LIO_LISBT-272 treatment improves mitochondrial stability, mobility and function C_LIO_LISBT-272 treatment reduces astrogliosis, microgliosis and improves UMN health C_LI

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Gautam, M., Genc, B., Helmold, B., Ahrens, A., Kuka, J., Makrecka-Kuka, M., Gunay, A., Kocak, N., Aguilar-Wickings, I. R., Keefe, D., Zheng, G., Swaminathan, S., Redmon, M., Zariwala, H. A., Ozdinler, P. H.. 2022-10-07. SBT-272 improves TDP-43 pathology in the ALS motor cortex by modulating mitochondrial integrity, motility, and function. https://doi.org/10.1101/2022.10.04.510854

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