The Role of the Microtubule Cytoskeleton in Neurodevelopmental Disorders

Lasser, Micaela; Tiber, Jessica; Lowery, Laura Anne

doi:10.3389/fncel.2018.00165

Cited by 169 publications

(161 citation statements)

References 219 publications

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“…The cell cytoskeleton provides shape and structural support (1,2) and consists of microfilaments, intermediate filaments and microtubules. Microtubules and actin filaments cooperate to facilitate the assembly, organization and remodeling of the cytoskeleton, which is critical for different stages of cellular development (3,4). Microtubules perform a variety of functions, including tracking intracellular trafficking, localizing organelles, mediating intracellular signals and maintaining cellular structure (5).…”

Section: Introductionmentioning

confidence: 99%

A nuclear localization signal is required for the nuclear translocation of Fign and its microtubule‑severing function

Cheng

et al. 2020

Mol Med Report

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It is commonly known that the specific function of a given ATPase associated with diverse cellular activities protein (i.e., a member of the AAA superfamily of proteins) depends primarily on its subcellular location. The microtubule-severing protein fidgetin (Fign) possesses a nuclear localization signal (NLS) that facilitates its translocation to the nucleus, where its assembly is finalized; here, Fign contributes to the regulation of microtubule configuration by cutting and trimming microtubule polymers. In the present study, Fign was found to be a nuclear protein, whose N-terminal sequence (SSLKRKAFYM; residues 314-323) acts as an NLS. Following substitution (KR to NN; 317-318) or deletion (NT; 314-323) mutations within the NLS, Fign, which is predominantly expressed in the nucleus, was found to reside in the cytoplasm of transfected cells. Furthermore, Fign was found to have an essential role in microtubule severing by preferentially targeting highly-tyrosinated microtubules (tyr-MTs). Mutation of the Fign NLS did not affect its microtubule-severing function or the cleavage of tyr-MTs, but did affect the cellular distribution of the Fign protein itself. Taken altogether, an NLS for Fign was identified, and it was demonstrated that the basic amino acids K317 and R318 are necessary for regulating its entry into the nucleus, whereas an increase in Fign in the cytosol due to mutations of the NLS did not affect its cleavage function.

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Section: Introductionmentioning

confidence: 99%

A nuclear localization signal is required for the nuclear translocation of Fign and its microtubule‑severing function

Cheng

et al. 2020

Mol Med Report

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“…A major target and effector of these signaling networks is the presynaptic microtubule (MT) cytoskeleton (Broadie & Richmond, ; Menon, Carrillo, & Zinn, ; Ruiz‐Cañada & Budnik, ). MTs have been linked to numerous neurodevelopmental and neurodegenerative disorders (Bodaleo & Gonzalez‐Billault, ; Goellner & Aberle, ; Lasser, Tiber, & Lowery, ; Matamoros & Baas, ). However, despite the clear importance of synaptic MTs, our understanding of their regulation and function still lags behind our comprehension of the upstream signaling pathways that orchestrate synapse development.…”

Section: Introductionmentioning

confidence: 99%

dTACC restricts bouton addition and regulates microtubule organization at the Drosophila neuromuscular junction

et al. 2019

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Regulation of the synaptic cytoskeleton is essential to proper neuronal development and wiring. Perturbations in neuronal microtubules (MTs) are associated with numerous pathologies, yet it remains unclear how changes in MTs may be coupled to synapse morphogenesis. Studies have identified many MT regulators that promote synapse growth. However, less is known about the factors that restrict growth, despite the potential links of synaptic overgrowth to severe neurological conditions. Here, we report that dTACC, which is implicated in MT assembly and stability, prevents synapse overgrowth at the Drosophila neuromuscular junction by restricting addition of new boutons throughout larval development. dTACC localizes to the axonal MT lattice and is required to maintain tubulin levels and the integrity of higher‐order MT structures in motor axon terminals. While previous reports have demonstrated the roles of MT‐stabilizing proteins in promoting synapse growth, our findings suggest that in certain contexts, MT stabilization may correlate with restricted growth.

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“…Key biomolecules with corresponding absorption and emission peak maxima (nm). Tryptophan 280 340 Collagen 339 380 NADH 340 440-460 Flavins 375 525 Tyrosine 275 303 microtubules may result in intellectual impairments and autism (108). The enzyme, NAD-dependent deacetylase sirtuin 2 (SIRT 2), which concentrates in neural tissue and is associated with diseases like Alzheimer's, Huntington's chorea and Parkinson's, deacetylates tubulin (109).…”

Section: Microtubulesmentioning

confidence: 99%

The Mystery of Chemotherapy Brain: Kynurenines, Tubulin and Biophoton Release

Sordillo

2020

Anticancer Res

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The majority of patients receiving chemotherapy experience post-chemotherapy cognitive impairment, sometimes referred to as "chemo brain" or "chemo fog." The cognitive impairment associated with this syndrome can be severe, and can sometimes last for many years after therapy discontinuation. Despite extensive investigations, its etiology is unknown. We argue that chemo brain results from damage to tubulin within microtubules. This damage can occur directly from tubulin inhibitors such as taxanes, epothilones or vinca alkaloids. Other chemotherapies stimulate increased mitochondrial activity and biophoton release. This results in abnormal tryptophan metabolism and excess production of neurotoxic kynurenines, which, in turn, damage microtubules.

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The Role of the Microtubule Cytoskeleton in Neurodevelopmental Disorders

Cited by 169 publications

References 219 publications

A nuclear localization signal is required for the nuclear translocation of Fign and its microtubule‑severing function

A nuclear localization signal is required for the nuclear translocation of Fign and its microtubule‑severing function

dTACC restricts bouton addition and regulates microtubule organization at the Drosophila neuromuscular junction

The Mystery of Chemotherapy Brain: Kynurenines, Tubulin and Biophoton Release

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