Looking for answers far away from the soma—the (un)known axonal functions of TDP-43, and their contribution to early NMJ disruption in ALS

Ionescu, Ariel; Altman, Topaz; Perlson, Eran

doi:10.1186/s13024-023-00623-6

Cited by 7 publications

(6 citation statements)

References 150 publications

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“…Muscle atrophy caused by loss of neuromuscular junctions (NMJs) and motor neurons is a hallmark of ALS [ 2 , 28 ]. We therefore analyzed the motor neurons, NMJ and muscle atrophy.…”

Section: Resultsmentioning

confidence: 99%

Mis-localization of endogenous TDP-43 leads to ALS-like early-stage metabolic dysfunction and progressive motor deficits

Hu,

Hruscha,

Pan

et al. 2024

Mol Neurodegeneration

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Background The key pathological signature of ALS/ FTLD is the mis-localization of endogenous TDP-43 from the nucleus to the cytoplasm. However, TDP-43 gain of function in the cytoplasm is still poorly understood since TDP-43 animal models recapitulating mis-localization of endogenous TDP-43 from the nucleus to the cytoplasm are missing. Methods CRISPR/Cas9 technology was used to generate a zebrafish line (called CytoTDP), that mis-locates endogenous TDP-43 from the nucleus to the cytoplasm. Phenotypic characterization of motor neurons and the neuromuscular junction was performed by immunostaining, microglia were immunohistochemically localized by whole-mount tissue clearing and muscle ultrastructure was analyzed by scanning electron microscopy. Behavior was investigated by video tracking and quantitative analysis of swimming parameters. RNA sequencing was used to identify mis-regulated pathways with validation by molecular analysis. Results CytoTDP fish have early larval phenotypes resembling clinical features of ALS such as progressive motor defects, neurodegeneration and muscle atrophy. Taking advantage of zebrafish’s embryonic development that solely relys on yolk usage until 5 days post fertilization, we demonstrated that microglia proliferation and activation in the hypothalamus is independent from food intake. By comparing CytoTDP to a previously generated TDP-43 knockout line, transcriptomic analyses revealed that mis-localization of endogenous TDP-43, rather than TDP-43 nuclear loss of function, leads to early onset metabolic dysfunction. Conclusions The new TDP-43 model mimics the ALS/FTLD hallmark of progressive motor dysfunction. Our results suggest that functional deficits of the hypothalamus, the metabolic regulatory center, might be the primary cause of weight loss in ALS patients. Cytoplasmic gain of function of endogenous TDP-43 leads to metabolic dysfunction in vivo that are reminiscent of early ALS clinical non-motor metabolic alterations. Thus, the CytoTDP zebrafish model offers a unique opportunity to identify mis-regulated targets for therapeutic intervention early in disease progression.

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“…Muscle atrophy caused by loss of neuromuscular junctions (NMJs) and motor neurons is a hallmark of ALS [ 2 , 28 ]. We therefore analyzed the motor neurons, NMJ and muscle atrophy.…”

Section: Resultsmentioning

confidence: 99%

Mis-localization of endogenous TDP-43 leads to ALS-like early-stage metabolic dysfunction and progressive motor deficits

Hu,

Hruscha,

Pan

et al. 2024

Mol Neurodegeneration

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“…miRNAs are a class of small, non-coding RNAs that play a crucial role in the regulation of genes and proteins involved in maintaining the integrity of the CNS. These miRNAs have significant roles in various processes, such as neural development, functional circuit formation, axonal regeneration at injury sites, and sensory axon regeneration ( Ionescu et al, 2023 ). Furthermore, the concurrent administration of axonal miRNAs and methylprednisolone reduces inflammation and augments expression of those genes related to ECM deposition.…”

Section: Combined Application Of Biomaterialsmentioning

confidence: 99%

Biomaterials targeting the microenvironment for spinal cord injury repair: progression and perspectives

Gao,

Wang,

et al. 2024

Front. Cell. Neurosci.

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Spinal cord injury (SCI) disrupts nerve pathways and affects sensory, motor, and autonomic function. There is currently no effective treatment for SCI. SCI occurs within three temporal periods: acute, subacute, and chronic. In each period there are different alterations in the cells, inflammatory factors, and signaling pathways within the spinal cord. Many biomaterials have been investigated in the treatment of SCI, including hydrogels and fiber scaffolds, and some progress has been made in the treatment of SCI using multiple materials. However, there are limitations when using individual biomaterials in SCI treatment, and these limitations can be significantly improved by combining treatments with stem cells. In order to better understand SCI and to investigate new strategies for its treatment, several combination therapies that include materials combined with cells, drugs, cytokines, etc. are summarized in the current review.

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“…Synaptic dysfunction is increasingly recognized as a converging mechanism in various genetic forms of ALS and FTD (Ling et al, 2013;Krishnamurthy et al, 2021;Gelon et al, 2022). Several genes linked to familial forms of ALS and FTD encode proteins that have roles at the synapse or are associated with synaptic function (Sephton and Yu, 2015;Gan et al, 2018;Casci et al, 2019;Ionescu et al, 2023).…”

Section: Synaptic Dysfunction As a Converging Mechanism In Als/ftdmentioning

confidence: 99%

Emerging perspectives of synaptic biomarkers in ALS and FTD

Krishnamurthy,

Pradhan

2024

Front. Mol. Neurosci.

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Amyotrophic Lateral Sclerosis (ALS) and Frontotemporal Dementia (FTD) are debilitating neurodegenerative diseases with shared pathological features like transactive response DNA-binding protein of 43 kDa (TDP-43) inclusions and genetic mutations. Both diseases involve synaptic dysfunction, contributing to their clinical features. Synaptic biomarkers, representing proteins associated with synaptic function or structure, offer insights into disease mechanisms, progression, and treatment responses. These biomarkers can detect disease early, track its progression, and evaluate therapeutic efficacy. ALS is characterized by elevated neurofilament light chain (NfL) levels in cerebrospinal fluid (CSF) and blood, correlating with disease progression. TDP-43 is another key ALS biomarker, its mislocalization linked to synaptic dysfunction. In FTD, TDP-43 and tau proteins are studied as biomarkers. Synaptic biomarkers like neuronal pentraxins (NPs), including neuronal pentraxin 2 (NPTX2), and neuronal pentraxin receptor (NPTXR), offer insights into FTD pathology and cognitive decline. Advanced technologies, like machine learning (ML) and artificial intelligence (AI), aid biomarker discovery and drug development. Challenges in this research include technological limitations in detection, variability across patients, and translating findings from animal models. ML/AI can accelerate discovery by analyzing complex data and predicting disease outcomes. Synaptic biomarkers offer early disease detection, personalized treatment strategies, and insights into disease mechanisms. While challenges persist, technological advancements and interdisciplinary efforts promise to revolutionize the understanding and management of ALS and FTD. This review will explore the present comprehension of synaptic biomarkers in ALS and FTD and discuss their significance and emphasize the prospects and obstacles.

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Looking for answers far away from the soma—the (un)known axonal functions of TDP-43, and their contribution to early NMJ disruption in ALS

Cited by 7 publications

References 150 publications

Mis-localization of endogenous TDP-43 leads to ALS-like early-stage metabolic dysfunction and progressive motor deficits

Mis-localization of endogenous TDP-43 leads to ALS-like early-stage metabolic dysfunction and progressive motor deficits

Biomaterials targeting the microenvironment for spinal cord injury repair: progression and perspectives

Emerging perspectives of synaptic biomarkers in ALS and FTD

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