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

Wali, Gautam; Sue, Carolyn M.; Mackay‐Sim, Alan

doi:10.3390/brainsci8080142

Cited by 12 publications

(12 citation statements)

References 99 publications

(153 reference statements)

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“…This work showed that microtubule destabilizing drugs including vinblastine attenuated the mutant spastin-associated phenotype, demonstrating the potential for mechanistic targeting. 85,86 Furthermore, use of vinblastine and nocodazole rescued focal axonal swellings associated with impaired axonal transport in cortical neurons from spastin knockout mice. 87 It is widely believed that SPG4 HSP is, in most cases, mediated by haploinsufficiency and partial loss of function in microtubule severing.…”

Section: Spg4 Hspmentioning

confidence: 96%

Hereditary spastic paraplegia: from diagnosis to emerging therapeutic approaches

Shribman

Reid

Crosby

et al. 2019

The Lancet Neurology

203

207

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Hereditary spastic paraplegia (HSP) describes a heterogeneous group of genetic neurodegenerative diseases characterised by progressive spasticity of the lower limbs. The pathogenic mechanism, associated clinical features and imaging abnormalities vary significantly according to the affected gene. Here, we describe the clinical and imaging characteristics of the more common forms of HSP. We discuss how to approach the diagnosis and management of a suspected case of HSP in the era of next generation sequencing, before discussing treatment and the potential of emerging therapeutic options for specific causes of HSP based on their underlying molecular mechanism.

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Section: Spg4 Hspmentioning

confidence: 96%

Hereditary spastic paraplegia: from diagnosis to emerging therapeutic approaches

Shribman

Reid

Crosby

et al. 2019

The Lancet Neurology

203

207

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“…In human patient-derived olfactory neurosphere-derived cells, SPAST mutations result in decreased levels of acetylated α-tubulin, a marker of stabilised microtubules, as well as reduced speed of peroxisome trafficking [ 106 ]. Tubulin binding drugs such as taxol, vinblastine, epothilone D and noscapine may increase acetylated alpha tubulin and thereby restore axonal transport, directly targeting the mechanism involved in SPG4 [ 106 , 107 ].…”

Section: Benefits Of a Genetic Diagnosis In Hspmentioning

confidence: 99%

“…Tubulin binding drugs such as taxol, vinblastine, epothilone D and noscapine may increase acetylated alpha tubulin and thereby restore axonal transport, directly targeting the mechanism involved in SPG4 [106,107]. Several genes associated with HSP phenotypes disturb lipid metabolic pathways as a potential therapeutic target, including CYP7B1, EPT1, PCYT2, DDHD1, DDHD2, PNPLA6, B4GALNT1, CYP2U1, FA2H, GBA2, PLA2G6, ATP13A2, BSCL2, C19orf12, ERLIN2, SPART, SPAST, SPG11, SPG15, ATL1 and REEP1 [108].…”

Section: Benefits Of a Genetic Diagnosis In Hspmentioning

confidence: 99%

Challenges and Controversies in the Genetic Diagnosis of Hereditary Spastic Paraplegia

Saputra¹,

Kumar

2021

Curr Neurol Neurosci Rep

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Purpose of Review The hereditary spastic paraplegias (HSPs) are a group of disorders characterised by progressive lower limb weakness and spasticity. We address the challenges and controversies involved in the genetic diagnosis of HSP. Recent Findings There is a large and rapidly expanding list of genes implicated in HSP, making it difficult to keep gene testing panels updated. There is also a high degree of phenotypic overlap between HSP and other disorders, leading to problems in choosing the right panel to analyse. We discuss genetic testing strategies for overcoming these diagnostic hurdles, including the use of targeted sequencing gene panels, whole-exome sequencing and whole-genome sequencing. Personalised treatments for HSP are on the horizon, and a genetic diagnosis may hold the key to access these treatments. Summary Developing strategies to overcome the challenges and controversies in HSP may hold the key to a rapid and accurate genetic diagnosis.

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“…However, the MT phenotypes observed in the Sp Δ mouse model could likewise be explained through the opposite role of spastin in promoting MT multiplication through generating nucleation seeds: in the absence of such a function, MT numbers might gradually decline and cause transport interruptions and eventually axonal pathology (see section on motor proteins; [214, 299]). Curiously, axon swellings in the Sp Δ mouse model were reduced with low doses of MT-stabilising or -destabilising drugs [65], thus failing to provide any clues as to whether spastin works through MT turn-over or amplification in this context.…”

Section: Potential Roles Of Severing Proteins and Mt-destabilising Kimentioning

confidence: 99%

The model of local axon homeostasis - explaining the role and regulation of microtubule bundles in axon maintenance and pathology

et al. 2019

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Axons are the slender, cable-like, up to meter-long projections of neurons that electrically wire our brains and bodies. In spite of their challenging morphology, they usually need to be maintained for an organism's lifetime. This makes them key lesion sites in pathological processes of ageing, injury and neurodegeneration. The morphology and physiology of axons crucially depends on the parallel bundles of microtubules (MTs), running all along to serve as their structural backbones and highways for life-sustaining cargo transport and organelle dynamics. Understanding how these bundles are formed and then maintained will provide important explanations for axon biology and pathology. Currently, much is known about MTs and the proteins that bind and regulate them, but very little about how these factors functionally integrate to regulate axon biology. As an attempt to bridge between molecular mechanisms and their cellular relevance, we explain here the model of local axon homeostasis, based on our own experiments in Drosophila and published data primarily from vertebrates/mammals as well as C. elegans. The model proposes that (1) the physical forces imposed by motor protein-driven transport and dynamics in the confined axonal space, are a life-sustaining necessity, but pose a strong bias for MT bundles to become disorganised. (2) To counterbalance this risk, MT-binding and-regulating proteins of different classes work together to maintain and protect MT bundles as necessary transport highways. Loss of balance between these two fundamental processes can explain the development of axonopathies, in particular those linking to MT-regulating proteins, motors and transport defects. With this perspective in mind, we hope that more researchers incorporate MTs into their work, thus enhancing our chances of deciphering the complex regulatory networks that underpin axon biology and pathology.

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

Cited by 12 publications

References 99 publications

Hereditary spastic paraplegia: from diagnosis to emerging therapeutic approaches

Hereditary spastic paraplegia: from diagnosis to emerging therapeutic approaches

Challenges and Controversies in the Genetic Diagnosis of Hereditary Spastic Paraplegia

The model of local axon homeostasis - explaining the role and regulation of microtubule bundles in axon maintenance and pathology

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