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

Gautam, Mukesh; Genç, Barış; Helmold, Benjamin; Ahrens, Angela; Kuka, Janis; Makrecka-Kūka, Marina; Gunay, Aksu; Koçak, Nuran; Aguilar-Wickings, Izaak R.; Keefe, Dennis; Zheng, Guozhu; Swaminathan, Suchitra; Redmon, Martin; Zariwala, Hatim A.; Özdinler, P. Hande

doi:10.1016/j.nbd.2023.106022

Cited by 11 publications

(8 citation statements)

References 98 publications

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“…Thus, the defects we find in mitochondrial respiration and ATP production could quickly lead to severe dysfunction and miscommunication with muscles and weakening of synapses. Concomitantly, it was recently shown that targeting mitochondria with a small molecule could improve upper motor neuron health in a TDP-43 mouse model (Gautam et al, 2023). The inability of ALS motor neurons to respond to high energy drains and the lack of compensatory glycolysis could render the motor neurons intrinsically more vulnerable as well as more dependent on glial support (Joseph Bloom et al;Lee et al, 2012).…”

Section: Discussionmentioning

confidence: 99%

Single cell RNA sequencing in isogenicFUSandTARDBPmutant ALS lines reveals early mitochondrial dysfunction as a common pathway in motor neurons

Schweingruber

Nijssen

Mechtersheimer

et al. 2023

Preprint

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Mutations in the RNA/DNA-binding proteins FUS and TDP-43 cause amyotrophic lateral sclerosis (ALS) with distinct neuropathological features. It is currently unclear how these gene mutations lead to selective motor neuron death and if there are common mechanisms across disease causations. Using single cell RNA sequencing of neurons derived from isogenic induced pluripotent stem cell lines, we show that motor neurons harbouring FUS P525L or FUS R495X mutations show a 4.9- to 15.5-fold larger transcriptional response than interneurons. About 20% (737 DEGs) of transcripts were coregulated across FUS R495X and P525L motor neurons and by comparing to a FUS knockout line we could discern that 48% (355 DEGs) were part of gain-of-function of FUS. Cross-comparing with isogenic TDP-43 M337V motor neurons, identified common mitochondrial dysfunction across FUS gain-of-function and TARDBP gene mutations, as did comparison with published RNA-Seq data from C9orf72-ALS motor neurons. Metabolic assessment confirmed a decrease in mitochondrial respiration and ATP turnover in mutant FUS and TARDBP lines and live cell microscopy showed a decrease in mitochondrial motility across ALS motor axons. Thus, we have identified early mitochondrial dysfunction in motor neurons shared across ALS-causative mutations, that could have major implications for their survival and which could be targeted therapeutically.

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Section: Discussionmentioning

confidence: 99%

Single cell RNA sequencing in isogenicFUSandTARDBPmutant ALS lines reveals early mitochondrial dysfunction as a common pathway in motor neurons

Schweingruber

Nijssen

Mechtersheimer

et al. 2023

Preprint

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“…However, there are preclinical studies of therapeutic compounds now beginning to address some of these shortcomings in targeting CSMN dysfunction. 198 By the same token that we have assessed interventions in well-established ALS-relevant pathways, new trials, including those that target nuclear export, TDP-43 mislocalization, and other RNA processing defects, among others, should not be judged solely on the basis of early phase studies that are upcoming.…”

Section: Discussionmentioning

confidence: 99%

“…Furthermore, in vitro models do not necessarily distinguish CSMN subtypes from nonspecific cortical neurons, in part because of a relative paucity of CSMN‐specific markers. However, there are preclinical studies of therapeutic compounds now beginning to address some of these shortcomings in targeting CSMN dysfunction 198 …”

Section: Discussionmentioning

confidence: 99%

Therapeutic targeting ofALSpathways: Refocusing an incomplete picture

Maragakis,

de Carvalho,

Weiss

2023

Ann Clin Transl Neurol

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Numerous potential amyotrophic lateral sclerosis (ALS)‐relevant pathways have been hypothesized and studied preclinically, with subsequent translation to clinical trial. However, few successes have been observed with only modest effects. Along with an improved but incomplete understanding of ALS as a neurodegenerative disease is the evolution of more sophisticated and diverse in vitro and in vivo preclinical modeling platforms, as well as clinical trial designs. We highlight proposed pathological pathways that have been major therapeutic targets for investigational compounds. It is likely that the failures of so many of these therapeutic compounds may not have occurred because of lack of efficacy but rather because of a lack of preclinical modeling that would help define an appropriate disease pathway, as well as a failure to establish target engagement. These challenges are compounded by shortcomings in clinical trial design, including lack of biomarkers that could predict clinical success and studies that are underpowered. Although research investments have provided abundant insights into new ALS‐relevant pathways, most have not yet been developed more fully to result in clinical study. In this review, we detail some of the important, well‐established pathways, the therapeutics targeting them, and the subsequent clinical design. With an understanding of some of the shortcomings in translational efforts over the last three decades of ALS investigation, we propose that scientists and clinicians may choose to revisit some of these therapeutic pathways reviewed here with an eye toward improving preclinical modeling, biomarker development, and the investment in more sophisticated clinical trial designs.

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“…Replenishing the NAD + pool with molecules such as nicotinamide mononucleotide and nicotinamide riboside shows preventive and therapeutic effects in age-related pathophysiology and disease conditions [ 384 – 387 ]. SBT-272, a novel molecule targeting the cardiolipin-rich IMM for normal mitochondrial structure, functions to restore mitochondrial structure and respiratory function in motor neurons of the ALS motor cortex [ 388 ]. Mitochondria-targeting antioxidants such as MitoQ, and antioxidant peptides like Bendavia (SS31) are protective against mitochondrial damage in brain diseases [ 389 – 391 ].…”

Section: Mitochondrial Therapies For Neurological Disordersmentioning

confidence: 99%

Focusing on mitochondria in the brain: from biology to therapeutics

Song,

Mei,

Wang

et al. 2024

Transl Neurodegener

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Mitochondria have multiple functions such as supplying energy, regulating the redox status, and producing proteins encoded by an independent genome. They are closely related to the physiology and pathology of many organs and tissues, among which the brain is particularly prominent. The brain demands 20% of the resting metabolic rate and holds highly active mitochondrial activities. Considerable research shows that mitochondria are closely related to brain function, while mitochondrial defects induce or exacerbate pathology in the brain. In this review, we provide comprehensive research advances of mitochondrial biology involved in brain functions, as well as the mitochondria-dependent cellular events in brain physiology and pathology. Furthermore, various perspectives are explored to better identify the mitochondrial roles in neurological diseases and the neurophenotypes of mitochondrial diseases. Finally, mitochondrial therapies are discussed. Mitochondrial-targeting therapeutics are showing great potentials in the treatment of brain diseases.

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

Cited by 11 publications

References 98 publications

Single cell RNA sequencing in isogenicFUSandTARDBPmutant ALS lines reveals early mitochondrial dysfunction as a common pathway in motor neurons

Single cell RNA sequencing in isogenicFUSandTARDBPmutant ALS lines reveals early mitochondrial dysfunction as a common pathway in motor neurons

Therapeutic targeting ofALSpathways: Refocusing an incomplete picture

Focusing on mitochondria in the brain: from biology to therapeutics

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