TDP-43 and Inflammation: Implications for Amyotrophic Lateral Sclerosis and Frontotemporal Dementia

Bright, Fiona; Chan, Gabriella; Hummel, Annika van; Ittner, Lars M.; Ke, Yazi D.

doi:10.3390/ijms22157781

Cited by 36 publications

(26 citation statements)

References 176 publications

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“…Activated microglia accompany neuronal degeneration and exacerbate neuronal loss. Microgliosis is well documented in the motor cortex of ALS, especially within the context of TDP-43 pathology (Appel et al, 2021; Bright et al, 2021; Jara et al, 2019; Jara et al, 2017). There was also increased microgliosis in prp-hTDP-43 A315T -UeGFP mice compared to WT healthy controls (WT-UeGFP+vehicle: 8.9±0.9, n =5; prp-hTDP-43 A315T -UeGFP+vehicle: 37.1±3.7, n =4, adjusted P <0.0001).…”

Section: Resultsmentioning

confidence: 99%

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

Gautam¹,

Genç²,

Helmold³

et al. 2022

Preprint

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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.

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Section: Resultsmentioning

confidence: 99%

“…Microgliosis is well documented in the motor cortex of ALS, especially within the context of TDP-43 pathology (Appel et al, 2021;Bright et al, 2021;Jara et al, 2019;Jara et al, 2017).…”

Section: Sbt-272 Treatment Reduces Astrogliosis and Microgliosis In T...mentioning

confidence: 99%

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

Gautam¹,

Genç²,

Helmold³

et al. 2022

Preprint

View full text Add to dashboard Cite

show abstract

“…Accumulation of cytoplasmic TDP-43 also represses the global protein synthesis in neuroblastoma models and FTD brain samples (Russo et al, 2017;Charif et al, 2020). In addition, a growing list of evidences indicate that TDP-43-induced neuroinflammation and innate immune responses are critically associated with the TDP-43 pathogenesis via NF-κβ/p65, cGAS-STING, NLRP3 inflammasome and PTP1B pathways (Zhao et al, 2015;Lee et al, 2020a;Dutta et al, 2020;Yu et al, 2020;Bright et al, 2021).…”

Section: Pathological Mechanisms Of Tdp-43mentioning

confidence: 99%

Functional implication of ubiquitinating and deubiquitinating mechanisms in TDP-43 proteinopathies

Tran

Lee

2022

Front. Cell Dev. Biol.

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Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease in which motor neurons in spinal cord and motor cortex are progressively lost. About 15% cases of ALS also develop the frontotemporal dementia (FTD), in which the frontotemporal lobar degeneration (FTLD) occurs in the frontal and temporal lobes of the brain. Among the pathologic commonalities in ALS and FTD is ubiquitin-positive cytoplasmic aggregation of TDP-43 that may reflect both its loss-of-function and gain-of-toxicity from proteostasis impairment. Deep understanding of how protein quality control mechanisms regulate TDP-43 proteinopathies still remains elusive. Recently, a growing body of evidence indicates that ubiquitinating and deubiquitinating pathways are critically engaged in the fate decision of aberrant or pathological TDP-43 proteins. E3 ubiquitin ligases coupled with deubiquitinating enzymes may influence the TDP-43-associated proteotoxicity through diverse events, such as protein stability, translocation, and stress granule or inclusion formation. In this article, we recapitulate our current understanding of how ubiquitinating and deubiquitinating mechanisms can modulate TDP-43 protein quality and its pathogenic nature, thus shedding light on developing targeted therapies for ALS and FTD by harnessing protein degradation machinery.

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“…These forms are evoked by FUS mutations, whose evidence suggests that the FUS protein may be a common component of clonotypic immune inclusions in non-SOD1 ALS [ 16 ]. Significant evidence concerning the role of clonotypic immunity and inflammation in ALS pathogeneses also emerges from the causative and susceptibility genes associated with the TDP-43 pathology, which are highly expressed in innate immune cells and increasingly implicated in key immune and inflammatory pathways, such as GRN and TBK1 [ 17 ].…”

Section: Recent Evidence On Clonotypic Immunity In Alsmentioning

confidence: 99%

Advances on Cellular Clonotypic Immunity in Amyotrophic Lateral Sclerosis

Schirò

Stefano²,

Iacono³

et al. 2022

Brain Sciences

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Amyotrophic lateral sclerosis (ALS) is a fatal neuromuscular disease, characterized by the progressive degeneration of the upper and lower motor neurons in the cortex and spinal cord. Although the pathogenesis of ALS remains unclear, evidence concerning the role of the clonotypic immune system is growing. Adaptive immunity cells often appear changed in number, or in terms of their activation profiles, both peripherally and centrally; however, their role in ALS appears conflictive. Data from human and animal model studies, which are currently reported in the literature, show that each subset of lymphocytes and their mediators may mediate a protective or toxic mechanism in ALS, affecting both its progression and risk of death. In the present review, an attempt is made to shed light on the actual role of cellular clonotypic immunity in ALS by integrating recent clinical studies and experimental observations.

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TDP-43 and Inflammation: Implications for Amyotrophic Lateral Sclerosis and Frontotemporal Dementia

Cited by 36 publications

References 176 publications

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

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

Functional implication of ubiquitinating and deubiquitinating mechanisms in TDP-43 proteinopathies

Advances on Cellular Clonotypic Immunity in Amyotrophic Lateral Sclerosis

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