Large-scale disruption of microtubule pathways in morphologically normal human spastin muscle

Molon, Annamaria; Giovanni, Simone Di; Chen, Y. W.; Clarkson, P. M.; Angelini, C.; Pegoraro, Elena; Hoffman, Eric P.

doi:10.1212/01.wnl.0000118204.90814.5a

Cited by 20 publications

(15 citation statements)

References 35 publications

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“…Presumably, SPAST mutations would affect organelle transport in all cells of the body, but with more profound effects in long axons that depend on microtubules alone for organelle transport. In agreement with this, is evidence that SPAST patient muscle is morphologically normal, despite similarly large magnitude changes in the transcriptome and disruption of microtubule pathways [69]. …”

Section: Patient-derived Stem Cell Models In Hspsupporting

confidence: 65%

Patient-Derived Stem Cell Models in SPAST HSP: Disease Modelling and Drug Discovery

2018

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Hereditary spastic paraplegia is an inherited, progressive paralysis of the lower limbs first described by Adolph Strümpell in 1883 with a further detailed description of the disease by Maurice Lorrain in 1888. Today, more than 100 years after the first case of HSP was described, we still do not know how mutations in HSP genes lead to degeneration of the corticospinal motor neurons. This review describes how patient-derived stem cells contribute to understanding the disease mechanism at the cellular level and use this for discovery of potential new therapeutics, focusing on SPAST mutations, the most common cause of HSP.

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Section: Patient-derived Stem Cell Models In Hspsupporting

confidence: 65%

Patient-Derived Stem Cell Models in SPAST HSP: Disease Modelling and Drug Discovery

2018

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“…Spastin is involved with microtubule disassembly (Errico et al, 2002) and is enriched in the distal axon of corticospinal motor neurons (reviewed in Salinas et al, 2007), the degeneration of which is seen post-mortem in the spinal cords of HSP patients, histologically (Deluca et al, 2004) and after magnetic imaging (Hedera et al, 2005). The cellular mechanisms whereby SPAST mutations cause axon degeneration are not understood but spastin mutations cause disrupted axonal transport (McDermott et al, 2003; Molon et al, 2004). Consistent with these findings, Spg4 mutant mice had gait abnormalities, axonal swellings in cortical axons in vitro and reduced anterograde axonal transport of mitochondria and β-amyloid precursor protein (APP)-containing membrane bound organelles (Kasher et al, 2009).…”

Section: Introductionmentioning

confidence: 99%

A patient-derived stem cell model of hereditary spastic paraplegia with SPAST mutations

Abrahamsen

Fan

Matigian

et al. 2013

Disease Models &Amp; Mechanisms

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SUMMARYHereditary spastic paraplegia (HSP) leads to progressive gait disturbances with lower limb muscle weakness and spasticity. Mutations in SPAST are a major cause of adult-onset, autosomal-dominant HSP. Spastin, the protein encoded by SPAST, is a microtubule-severing protein that is enriched in the distal axon of corticospinal motor neurons, which degenerate in HSP patients. Animal and cell models have identified functions of spastin and mutated spastin but these models lack the gene dosage, mutation variability and genetic background that characterize patients with the disease. In this study, this genetic variability is encompassed by comparing neural progenitor cells derived from biopsies of the olfactory mucosa from healthy controls with similar cells from HSP patients with SPAST mutations, in order to identify cell functions altered in HSP. Patient-derived cells were similar to control-derived cells in proliferation and multiple metabolic functions but had major dysregulation of gene expression, with 57% of all mRNA transcripts affected, including many associated with microtubule dynamics. Compared to control cells, patient-derived cells had 50% spastin, 50% acetylated α-tubulin and 150% stathmin, a microtubule-destabilizing enzyme. Patient-derived cells were smaller than control cells. They had altered intracellular distributions of peroxisomes and mitochondria and they had slower moving peroxisomes. These results suggest that patient-derived cells might compensate for reduced spastin, but their increased stathmin expression reduced stabilized microtubules and altered organelle trafficking. Sub-nanomolar concentrations of the microtubule-binding drugs, paclitaxel and vinblastine, increased acetylated α-tubulin levels in patient cells to control levels, indicating the utility of this cell model for screening other candidate compounds for drug therapies.

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“…Overexpression of spastin in Drosophila neuromusculature (Sherwood et al, 2004;Trotta et al, 2004) and in cultured cells (Errico et al, 2002;Roll-Mecak and Vale, 2005) caused dramatically fragmented and reduced MTs. Surprisingly, morphologically normal muscles are present in patients with spastin mutations, although large-scale disruption of MT pathways was detected at the molecular level (Molon et al, 2004). No MT defects were reported in a mouse model in which the endogenous spastin is truncated (Tarrade et al, 2006).…”

Section: Tbce Antagonizes Spastin In Regulating Mt Dynamicsmentioning

confidence: 99%

DrosophilaTubulin-specific chaperone E functions at neuromuscular synapses and is required for microtubule network formation

et al. 2009

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Hypoparathyroidism, mental retardation and facial dysmorphism (HRD) is a fatal developmental disease caused by mutations in tubulin-specific chaperone E (TBCE). A mouse Tbce mutation causes progressive motor neuronopathy. To dissect the functions of TBCE and the pathogenesis of HRD, we generated mutations in Drosophila tbce, and manipulated its expression in a tissue-specific manner. Drosophila tbce nulls are embryonic lethal. Tissue-specific knockdown and overexpression of tbce in neuromusculature resulted in disrupted and increased microtubules, respectively. Alterations in TBCE expression also affected neuromuscular synapses. Genetic analyses revealed an antagonistic interaction between TBCE and the microtubule-severing protein Spastin. Moreover, treatment of muscles with the microtubule-depolymerizing drug nocodazole implicated TBCE as a tubulin polymerizing protein.Taken together, our results demonstrate that TBCE is required for the normal development and function of neuromuscular synapses and that it promotes microtubule formation. As defective microtubules are implicated in many neurological and developmental diseases, our work on TBCE may offer novel insights into their basis.

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Large-scale disruption of microtubule pathways in morphologically normal human spastin muscle

Cited by 20 publications

References 35 publications

Patient-Derived Stem Cell Models in SPAST HSP: Disease Modelling and Drug Discovery

Patient-Derived Stem Cell Models in SPAST HSP: Disease Modelling and Drug Discovery

A patient-derived stem cell model of hereditary spastic paraplegia with SPAST mutations

DrosophilaTubulin-specific chaperone E functions at neuromuscular synapses and is required for microtubule network formation

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