Reference Report

Reference
Citation	Du, F., Ozdowski, E.F., Kotowski, I.K., Marchuk, D.A., Sherwood, N.T. (2010). Functional conservation of human Spastin in a Drosophila model of autosomal dominant-hereditary spastic paraplegia. Hum. Mol. Genet. 19(10): 1883--1896. (Export to RIS)
FlyBase ID	FBrf0210700
Publication Type	Research paper
PubMed ID	20154342
PubMed Abstract	Mutations in spastin are the most frequent cause of the neurodegenerative disease autosomal dominant-hereditary spastic paraplegia (AD-HSP). Drosophila melanogaster lacking spastin exhibit striking behavioral similarities to human patients suffering from AD-HSP, suggesting conservation of Spastin function between the species. Consistent with this, we show that exogenous expression of wild-type Drosophila or human spastin rescues behavioral and cellular defects in spastin null flies equivalently. This enabled us to generate genetically representative models of AD-HSP, which arises from dominant mutations in spastin rather than a complete loss of the gene. Flies co-expressing one copy of wild-type human spastin and one encoding the K388R catalytic domain mutation in the fly spastin null background, exhibit aberrant distal synapse morphology and microtubule distribution, similar to but less severe than spastin nulls. R388 or a separate nonsense mutation act dominantly and are furthermore sufficient to confer partial rescue, supporting in vitro evidence for additional, non-catalytic Spastin functions. Using this model, we tested the observation from human pedigrees that S44L and P45Q are trans-acting modifiers of mutations affecting the Spastin catalytic domain. As in humans, both L44 and Q45 are largely silent when heterozygous, but exacerbate mutant phenotypes when expressed in trans with R388. These transgenic 'AD-HSP' flies therefore provide a powerful and tractable model to enhance our understanding of the cellular and behavioral consequences of human spastin mutations and test hypotheses directly relevant to the human disease.
DOI	10.1093/hmg/ddq064
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Language of Publication	English
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Publication Type	Journal
Abbreviation	Hum. Mol. Genet.
Title	Human Molecular Genetics
Publication Year	1992-
ISBN/ISSN	0964-6906
Data from Reference
Alleles (12)
	Hsap\SPAST^{L44.Scer\UAS.T:Avic\GFP-CFP} Hsap\SPAST^Q45.Scer\UAS Hsap\SPAST^{R388.Scer\UAS.T:Avic\GFP-YFP.Venus} Hsap\SPAST^{R431STOP.Scer\UAS} Hsap\SPAST^{Scer\UAS.T:Avic\GFP-YFP.Venus} Scer\GAL4^{elav.Switch.PO} Scer\GAL4^en-e16E Scer\GAL4^how-24B spas^5.75 spas^{Scer\UAS.T:Avic\GFP-CFP} T:Avic\GFP^CFP T:Avic\GFP^YFP.Venus
Constructs (7)
	P{elav-Switch.O} P{UAS-spas.CFP} P{UAS-SPAST.L44.CFP} P{UAS-SPAST.Q45} P{UAS-SPAST.R388.YFP} P{UAS-SPAST.R431STOP.YFP} P{UAS-SPAST.YFP}
Genes (4)
	futsch Hsap\SPAST Scer\GAL4 spas
Insertions (2)
	P{en2.4-GAL4}e16E P{GawB}how^24B
Natural transposons (1)
	P-element