NDLI: Spastic Paraplegia Mutation N256S in the Neuronal Microtubule Motor KIF5A Disrupts Axonal Transport in a Drosophila HSP Model

Content Provider	PubMed Central
Author	Petra, Füger Sreekumar, Vrinda Schüle, Rebecca Kern, Jeannine V. Stanchev, Doychin T. Schneider, Carola D. Karle, Kathrin N. Daub, Katharina J. Siegert, Vera K. Matthias, Flötenmeyer Schwarz, Heinz Schöls, Ludger Rasse, Tobias M.
Editor	Copenhaver, Gregory P.
Copyright Year	2012
Abstract	Hereditary spastic paraplegias (HSPs) comprise a group of genetically heterogeneous neurodegenerative disorders characterized by spastic weakness of the lower extremities. We have generated a Drosophila model for HSP type 10 (SPG10), caused by mutations in KIF5A. KIF5A encodes the heavy chain of kinesin-1, a neuronal microtubule motor. Our results imply that SPG10 is not caused by haploinsufficiency but by the loss of endogenous kinesin-1 function due to a selective dominant-negative action of mutant KIF5A on kinesin-1 complexes. We have not found any evidence for an additional, more generalized toxicity of mutant Kinesin heavy chain (Khc) or the affected kinesin-1 complexes. Ectopic expression of Drosophila Khc carrying a human SPG10-associated mutation (N256S) is sufficient to disturb axonal transport and to induce motoneuron disease in Drosophila. Neurofilaments, which have been recently implicated in SPG10 disease manifestation, are absent in arthropods. Impairments in the transport of kinesin-1 cargos different from neurofilaments are thus sufficient to cause HSP–like pathological changes such as axonal swellings, altered structure and function of synapses, behavioral deficits, and increased mortality.
Related Links	http://dx.doi.org/10.1371/journal.pgen.1003066
Starting Page	1003066
File Format	PDF
ISSN	15537404
e-ISSN	15537404
Journal	PLoS Genetics
Issue Number	11
Volume Number	8
Language	English
Publisher	Public Library of Science
Publisher Date	2012-11-01
Access Restriction	Open
Rights Holder	Public Library of Science
Subject Keyword	Research in Higher Education
Content Type	Text
Resource Type	Article
Subject	Genetics Molecular Biology Cancer Research Ecology, Evolution, Behavior and Systematics Genetics (clinical)

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Spastic Paraplegia Mutation N256S in the Neuronal Microtubule Motor KIF5A Disrupts Axonal Transport in a Drosophila HSP Model

Correction: Spastic Paraplegia Mutation N256S in the Neuronal Microtubule Motor KIF5A Disrupts Axonal Transport in a Drosophila HSP Model

Axonal transport deficit in a KIF5A –/– mouse model

Axonal transport deficit in a KIF5A –/– mouse model

A hereditary spastic paraplegia mutation in kinesin-1A/KIF5A disrupts neurofilament transport

A hereditary spastic paraplegia mutation in kinesin-1A/KIF5A disrupts neurofilament transport

Mutation in KIF5A can also cause adult-onset hereditary spastic paraplegia

The Genetics of Axonal Transport and Axonal Transport Disorders

A Hereditary Spastic Paraplegia Mouse Model Supports a Role of ZFYVE26/SPASTIZIN for the Endolysosomal System

Spastic Paraplegia Mutation N256S in the Neuronal Microtubule Motor KIF5A Disrupts Axonal Transport in a Drosophila HSP Model

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Spastic Paraplegia Mutation N256S in the Neuronal Microtubule Motor KIF5A Disrupts Axonal Transport in a Drosophila HSP Model

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