Live axonal transport disruption by mutant huntingtin fragments in Drosophila motor neuron axons

Sinadinos, Christopher; Burbidge-King, T.; Soh, Daniel; Thompson, Leslie M.; Marsh, J. Lawrence; Wyttenbach, Andreas; Mudher, Amritpal

doi:10.1016/j.nbd.2009.02.012

Cited by 53 publications

(29 citation statements)

References 33 publications

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“…Larvae were left to develop to L3 wandering stage (day 5). Axonal transport analysis was conducted as previously described1165. Briefly, L3 larvae were anaesthetised in diethylether vapour for 15 min, immobilised on glass slides in 1% agarose ventral face up and mounted under coverslips.…”

Section: Methodsmentioning

confidence: 99%

Microtubule stabilising peptides rescue tau phenotypes in-vivo

Quraishe

Sealey

Cranfield

et al. 2016

Sci Rep

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The microtubule cytoskeleton is a highly dynamic, filamentous network underpinning cellular structure and function. In Alzheimer’s disease, the microtubule cytoskeleton is compromised, leading to neuronal dysfunction and eventually cell death. There are currently no disease-modifying therapies to slow down or halt disease progression. However, microtubule stabilisation is a promising therapeutic strategy that is being explored. We previously investigated the disease-modifying potential of a microtubule-stabilising peptide NAP (NAPVSIPQ) in a well-established Drosophila model of tauopathy characterised by microtubule breakdown and axonal transport deficits. NAP prevented as well as reversed these phenotypes even after they had become established. In this study, we investigate the neuroprotective capabilities of an analogous peptide SAL (SALLRSIPA). We found that SAL mimicked NAP’s protective effects, by preventing axonal transport disruption and improving behavioural deficits, suggesting both NAP and SAL may act via a common mechanism. Both peptides contain a putative ‘SIP’ (Ser-Ile-Pro) domain that is important for interactions with microtubule end-binding proteins. Our data suggests this domain may be central to the microtubule stabilising function of both peptides and the mechanism by which they rescue phenotypes in this model of tauopathy. Our observations support microtubule stabilisation as a promising disease-modifying therapeutic strategy for tauopathies like Alzheimer’s disease.

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Section: Methodsmentioning

confidence: 99%

Microtubule stabilising peptides rescue tau phenotypes in-vivo

Quraishe

Sealey

Cranfield

et al. 2016

Sci Rep

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“…When mutant Htt ex1 was co-expressed with fluorescent axonal transport proteins, altered trafficking of organelles and proteins, including synaptic vesicles, could be observed. 31 Axonal transport defects have also been found in mouse models of HD. The R6/2 exon 1 model has Htt inclusions blocking neurites, along with axonal degeneration.…”

Section: Axonal Transport Defects In Drosophila Models Of Huntington mentioning

confidence: 99%

Modeling Huntington disease in Drosophila

Krench

Littleton

2013

Fly

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“…The polyQ aggregates physically block transport in narrow axons. Truncated versions of huntingtin, ataxin-3 or the androgen receptor inhibit anterograde and retrograde transport in giant squid axons, mammalian tissue culture cells and fly models of HD (Gunawardena et al 2003;Szebenyi et al 2003;Lee et al 2004;Kaltenbach et al 2007;Sinadinos et al 2009). Mutant polyQ proteins interact aberrantly with transport pathway proteins and thus titrate them away from their normal transport functions (Gunawardena et al 2003;Lee et al 2004).…”

Section: Axonal Transport Defects In Polyq Diseasesmentioning

confidence: 99%

Modifiers and mechanisms of multi-system polyglutamine neurodegenerative disorders: lessons from fly models

Mallik

Lakhotia

2010

J Genet

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Polyglutamine (polyQ) diseases, resulting from a dynamic expansion of glutamine repeats in a polypeptide, are a class of genetically inherited late onset neurodegenerative disorders which, despite expression of the mutated gene widely in brain and other tissues, affect defined subpopulations of neurons in a disease-specific manner. We briefly review the different polyQ-expansion-induced neurodegenerative disorders and the advantages of modelling them in Drosophila. Studies using the fly models have successfully identified a variety of genetic modifiers and have helped in understanding some of the molecular events that follow expression of the abnormal polyQ proteins. Expression of the mutant polyQ proteins causes, as a consequence of intra-cellular and inter-cellular networking, mis-regulation at multiple steps like transcriptional and posttranscriptional regulations, cell signalling, protein quality control systems (protein folding and degradation networks), axonal transport machinery etc., in the sensitive neurons, resulting ultimately in their death. The diversity of genetic modifiers of polyQ toxicity identified through extensive genetic screens in fly and other models clearly reflects a complex network effect of the presence of the mutated protein. Such network effects pose a major challenge for therapeutic applications.

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Live axonal transport disruption by mutant huntingtin fragments in Drosophila motor neuron axons

Cited by 53 publications

References 33 publications

Microtubule stabilising peptides rescue tau phenotypes in-vivo

Microtubule stabilising peptides rescue tau phenotypes in-vivo

Modeling Huntington disease in Drosophila

Modifiers and mechanisms of multi-system polyglutamine neurodegenerative disorders: lessons from fly models

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