Multiple roles for the cytoskeleton in ALS

Liu, Xinbei; Henty-Ridilla, Jessica L.

doi:10.1016/j.expneurol.2022.114143

Cited by 19 publications

(18 citation statements)

References 161 publications

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“…TUBA4A, a known ALS gene ( Smith et al, 2014 ), encodes α-tubulin and mutations in T145 and W407 near the α-tubulin binding sequence may affect microtubule heterodimer formation ( Liu and Henty-Ridilla, 2022 ). Similarly, an exome sequencing study confirmed that overexpression of α-tubulin with W407X mutation severely affect inter-microtubule aggregation and track formation ( Smith et al, 2014 ).…”

Section: Axonal Transport Defects In Neurodegenerative Diseasesmentioning

confidence: 99%

Common mechanisms underlying axonal transport deficits in neurodegenerative diseases: a mini review

Yang

Lian

et al. 2023

Front. Mol. Neurosci.

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Many neurodegenerative diseases including Alzheimer’s disease, Parkinson’s disease, and amyotrophic lateral sclerosis are characterized by the accumulation of pathogenic proteins and abnormal localization of organelles. These pathological features may be related to axonal transport deficits in neurons, which lead to failures in pathological protein targeting to specific sites for degradation and organelle transportation to designated areas needed for normal physiological functioning. Axonal transport deficits are most likely early pathological events in such diseases and gradually lead to the loss of axonal integrity and other degenerative changes. In this review, we investigated reports of mechanisms underlying the development of axonal transport deficits in a variety of common neurodegenerative diseases, such as Alzheimer’s disease, amyotrophic lateral sclerosis, Parkinson’s disease and Huntington’s disease to provide new ideas for therapeutic targets that may be used early in the disease process. The mechanisms can be summarized as follows: (1) motor protein changes including expression levels and post-translational modification alteration; (2) changes in microtubules including reducing stability and disrupting tracks; (3) changes in cargoes including diminished binding to motor proteins. Future studies should determine which axonal transport defects are disease-specific and whether they are suitable therapeutic targets in neurodegenerative diseases.

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Section: Axonal Transport Defects In Neurodegenerative Diseasesmentioning

confidence: 99%

Common mechanisms underlying axonal transport deficits in neurodegenerative diseases: a mini review

Yang

Lian

et al. 2023

Front. Mol. Neurosci.

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“…Various dysregulated proteins from our study were reported to be involved in amyotrophic lateral sclerosis (ALS). REEP1 cooperates with Ndufa4 in a mechanism that protects the integrity of mitochondrial complex IV, which is linked to ALS [ 82 , 83 , 84 , 85 ]. Bunina bodies are found in ALS, showing that Psap may also be a part of Bunina bodies.…”

Section: Discussionmentioning

confidence: 99%

Hypoxic Preconditioned Neural Stem Cell-Derived Extracellular Vesicles Contain Distinct Protein Cargo from Their Normal Counterparts

Gharbi

Liu

Khan

et al. 2023

CIMB

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Hypoxic preconditioning has been demonstrated to increase the resistance of neural stem cells (NSCs) to hypoxic conditions, as well as to improve their capacity for differentiation and neurogenesis. Extracellular vesicles (EVs) have recently emerged as critical mediators of cell–cell communication, but their role in this hypoxic conditioning is presently unknown. Here, we demonstrated that three hours of hypoxic preconditioning triggers significant neural stem cell EV release. Proteomic profiling of EVs from normal and hypoxic preconditioned neural stem cells identified 20 proteins that were upregulated and 22 proteins that were downregulated after hypoxic preconditioning. We also found an upregulation of some of these proteins by qPCR, thus indicating differences also at the transcript level within the EVs. Among the upregulated proteins are CNP, Cyfip1, CASK, and TUBB5, which are well known to exhibit significant beneficial effects on neural stem cells. Thus, our results not only show a significant difference of protein cargo in EVs consequent to hypoxic exposure, but identify several candidate proteins that might play a pivotal role in the cell-to-cell mediated communication underlying neuronal differentiation, protection, maturation, and survival following exposure to hypoxic conditions.

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“…ALS/FTD has also been linked to changes in axonal cytoskeletal organisation. While ALS has been repeatedly linked to changes in axonal transport, less is known about changes in axonal actin, which are more challenging to study (Liu and Henty-Ridilla, 2022). Intriguingly, mutations in α-tubulin 4A are associated with familial ALS, ALS-FTD, and FTD (Mol et al, 2021; Smith et al, 2014), but patients with mutations in the actin polymerisation-regulating protein profilin-1 (PFN1) commonly display only ALS-like symptoms (Ingre et al, 2013; Wu et al, 2012).…”

Section: Introductionmentioning

confidence: 99%

“…The relative contribution of actin and microtubule deregulation in ALS/FTD is under investigation (Liu and Henty-Ridilla, 2022), and has not been delineated for FUS-ALS/FTD.…”

Section: Introductionmentioning

confidence: 99%

“…The relative contribution of actin and microtubule deregulation in ALS/FTD is under investigation (Liu and Henty-Ridilla, 2022), and has not been delineated for FUS-ALS/FTD. It has been argued that microtubules are particularly vulnerable in ALS, causing transport deficits (Clark et al, 2016; De Vos and Hafezparast, 2017), but also that the neuromuscular junction may be especially vulnerable to changes in actin, given that it is the largest synapse (Hensel and Claus, 2017).…”

Section: Introductionmentioning

confidence: 99%

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Mutation of the ALS/FTD-associated RNA-binding protein FUS alters axonal cytoskeletal organisation

Tartwijk

Wunderlich

Mela

et al. 2022

Preprint

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Aberrant condensation and localisation of the RNA-binding protein fused in sarcoma (FUS) occur in variants of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). ALS is also associated with cytoskeletal defects, genetically and through observations of compromised axonal transport. Here, we asked whether compromised axonal cytoskeletal organisation is an early feature of FUS-associated ALS/FTD. We used an ALS-associated mutant FUS(P525L) and the FTD-mimic hypomethylated FUS, FUS(16R), to investigate the common and distinct cytoskeletal changes found in these two reported Xenopus models. Combining a novel atomic force microscopy (AFM)-based approach for in vitro cytoskeletal characterisation and in vivo axonal branching analysis, we found that mutant FUS reduced actin density in the dynamically remodelling growth cone, and reduced axonal branch complexity. We furthermore found evidence of an axon looping defect for FUS(P525L). Therefore, we show that compromised actin remodelling is potentially an important early event in FUS-associated pathogenesis.

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Multiple roles for the cytoskeleton in ALS

Cited by 19 publications

References 161 publications

Common mechanisms underlying axonal transport deficits in neurodegenerative diseases: a mini review

Common mechanisms underlying axonal transport deficits in neurodegenerative diseases: a mini review

Hypoxic Preconditioned Neural Stem Cell-Derived Extracellular Vesicles Contain Distinct Protein Cargo from Their Normal Counterparts

Mutation of the ALS/FTD-associated RNA-binding protein FUS alters axonal cytoskeletal organisation

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