Axonal TDP-43 condensates drive neuromuscular junction disruption through inhibition of local synthesis of nuclear encoded mitochondrial proteins

Altman, Topaz; Ionescu, Ariel; Ibraheem, Amjad; Priesmann, Dominik; Gradus-Pery, Tal; Farberov, Luba; Alexandra, Gayster; Shelestovich, Natalia; Dafinca, Ruxandra; Shomron, Noam; Rage, Florence; Talbot, Kevin; Ward, Michael E.; Dori, Amir; Krüger, Marcus; Perlson, Eran

doi:10.1038/s41467-021-27221-8

Cited by 78 publications

(118 citation statements)

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“…As mentioned in the Transport Granules section, TDP-43 phase separation is important to facilitate local translation of mRNA at dendrites and axons through transport granules. However, a recent article by Altman et al suggests that TDP-43 phase separation causes decreased mitochondrial protein translation in axons and at the neuromuscular junction (Altman et al, 2021), thus adding nuance to the functional role of phase-separated TDP-43 in neurons and calls for further investigation.…”

Section: Discussionmentioning

confidence: 99%

“…ALS-linked TDP-43 mutations lead to decreased interaction with mRNA, reduced RNP granule dynamics and disrupted axonal transport dynamics (Alami et al, 2014;Ishiguro et al, 2016;Gopal et al, 2017;Endo et al, 2018;Thelen and Kye, 2019), implicating TDP-43's role in local translation. Mislocalized TDP-43 can also affect local translation in axons by promoting G3BP1-positive RNP condensate assembly, consequently inhibiting local protein synthesis (Altman et al, 2021). Similarly, FUS is involved in neuronal transport granules.…”

Section: Transport Granules and Local Translationmentioning

confidence: 99%

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Liquid-Liquid Phase Separation of TDP-43 and FUS in Physiology and Pathology of Neurodegenerative Diseases

Carey

Guo

2022

Front. Mol. Biosci.

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Liquid-liquid phase separation of RNA-binding proteins mediates the formation of numerous membraneless organelles with essential cellular function. However, aberrant phase transition of these proteins leads to the formation of insoluble protein aggregates, which are pathological hallmarks of neurodegenerative diseases including ALS and FTD. TDP-43 and FUS are two such RNA-binding proteins that mislocalize and aggregate in patients of ALS and FTD. They have similar domain structures that provide multivalent interactions driving their phase separation in vitro and in the cellular environment. In this article, we review the factors that mediate and regulate phase separation of TDP-43 and FUS. We also review evidences that connect the phase separation property of TDP-43 and FUS to their functional roles in cells. Aberrant phase transition of TDP-43 and FUS leads to protein aggregation and disrupts their regular cell function. Therefore, restoration of functional protein phase of TDP-43 and FUS could be beneficial for neuronal cells. We discuss possible mechanisms for TDP-43 and FUS aberrant phase transition and aggregation while reviewing the methods that are currently being explored as potential therapeutic strategies to mitigate aberrant phase transition and aggregation of TDP-43 and FUS.

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Section: Discussionmentioning

confidence: 99%

Section: Transport Granules and Local Translationmentioning

confidence: 99%

Liquid-Liquid Phase Separation of TDP-43 and FUS in Physiology and Pathology of Neurodegenerative Diseases

Carey

Guo

2022

Front. Mol. Biosci.

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“…In 2021, a new mechanism causing nerve destruction in ALS was discovered: TDP-43 protein accumulates and aggregates in axons and neuromuscular junctions to toxic assemblies. These TDP-43 amyloids inhibit the local synthesis of mitochondrial proteins, and thus, disrupt the neuromuscular junctions [52].…”

Section: Neuroinflammation In Different Neurodegenerative Diseases: C...mentioning

confidence: 99%

Novel Therapeutic Target for Prevention of Neurodegenerative Diseases: Modulation of Neuroinflammation with Sig-1R Ligands

2022

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Neurodegenerative diseases (NDDs) are characterized by progressive deterioration of the structure and function of cells and their networks in the nervous system. There are currently no drugs or other treatments that can stop the progression of NDDs. NDDs have many similarities and common pathways, e.g., formation of misfolded amyloid proteins, intra- and extracellular amyloid deposits, and chronic inflammation. Initially, the inflammation process has a cytoprotective function; however, an elevated and prolonged immune response has damaging effects and causes cell death. Neuroinflammation has been a target of drug development for treating and curing NDDs. Treatment of different NDDs with non-steroid anti-inflammatory drugs (NSAIDs) has failed or has given inconsistent results. The use of NSAIDs in diagnosed Alzheimer’s disease is currently not recommended. Sigma-1 receptor (Sig-1R) is a novel target for NDD drug development. Sig-1R plays a key role in cellular stress signaling, and it regulates endoplasmic reticulum stress and unfolded protein response. Activation of Sig-1R provides neuroprotection in cell cultures and animal studies. Clinical trials demonstrated that several Sig-1R agonists (pridopidine, ANAVEX3-71, fluvoxamine, dextrometorphan) and their combinations have a neuroprotective effect and slow down the progression of distinct NDDs.

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“…Many paradigms implicate the association of neurodegenerative diseases with infectious diseases and the putative biological function of some of the primary proteins implicated in these disorders. The aberrant accumulation of specific proteins, such as TDP-43 [16] and SOD1 [17] in ALS, amyloid β [18] and Tau [19] in AD, and α-synuclein [20] in PD, with similar proteinopathies seen in the chronic stage of ischemic stroke [21] can initiate a cascade of deleterious innate immunity processes that may contribute to the dysbiotic and dysfunctional GBA pathophysiological manifestations of NDDs. Recent review papers highlight the interaction between GBA and NDDs, with emphasis on diet, exercise, prebiotics and probiotics as treatments towards maintaining healthy microbiota in GBA [22][23][24][25][26][27].…”

Section: Introductionmentioning

confidence: 99%

Gut–Brain Axis as a Pathological and Therapeutic Target for Neurodegenerative Disorders

Toledo

Monroy

Salazar

et al. 2022

IJMS

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Human lifestyle and dietary behaviors contribute to disease onset and progression. Neurodegenerative diseases (NDDs), considered multifactorial disorders, have been associated with changes in the gut microbiome. NDDs display pathologies that alter brain functions with a tendency to worsen over time. NDDs are a worldwide health problem; in the US alone, 12 million Americans will suffer from NDDs by 2030. While etiology may vary, the gut microbiome serves as a key element underlying NDD development and prognosis. In particular, an inflammation-associated microbiome plagues NDDs. Conversely, sequestration of this inflammatory microbiome by a correction in the dysbiotic state of the gut may render therapeutic effects on NDDs. To this end, treatment with short-chain fatty acid-producing bacteria, the main metabolites responsible for maintaining gut homeostasis, ameliorates the inflammatory microbiome. This intimate pathological link between the gut and NDDs suggests that the gut-brain axis (GBA) acts as an underexplored area for developing therapies for NDDs. Traditionally, the classification of NDDs depends on their clinical presentation, mostly manifesting as extrapyramidal and pyramidal movement disorders, with neuropathological evaluation at autopsy as the gold standard for diagnosis. In this review, we highlight the evolving notion that GBA stands as an equally sensitive pathological marker of NDDs, particularly in Alzheimer’s disease, Parkinson’s disease, amyotrophic lateral sclerosis and chronic stroke. Additionally, GBA represents a potent therapeutic target for treating NDDs.

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Axonal TDP-43 condensates drive neuromuscular junction disruption through inhibition of local synthesis of nuclear encoded mitochondrial proteins

Cited by 78 publications

References 68 publications

Liquid-Liquid Phase Separation of TDP-43 and FUS in Physiology and Pathology of Neurodegenerative Diseases

Liquid-Liquid Phase Separation of TDP-43 and FUS in Physiology and Pathology of Neurodegenerative Diseases

Novel Therapeutic Target for Prevention of Neurodegenerative Diseases: Modulation of Neuroinflammation with Sig-1R Ligands

Gut–Brain Axis as a Pathological and Therapeutic Target for Neurodegenerative Disorders

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