Intracellular membrane traffic in hereditary spastic paraplegias. (360G-Wellcome-073483_Z_03_A)

£180,069

In humans, the main pathway over which voluntary motor signals are carried from the brain to the spinal cord is the corticospinal tract. Insults to the "upper motor neurons" that constitute this tract can result in a clinical picture of spastic paralysis. The hereditary spastic paraplegias (HSPs) are single gene disorders in which the axons of the corticospinal tract show progressive, length-dependant, distal degeneration after initially normal development. Functional characterisation of the responsible genes is therefore likely to reveal cellular processes that are important in long tract axonal maintenance and perhaps of relevance to common neurological diseases. More than 20 HSP loci exist and 9 of the responsible genes have been identified. Until recently, there was no discernable common underlying cellular pathological mechanism for groups of HSP conditions. However, several lines of evidence now point to defects in intracellular traffic as being the underlying cause of several different genetic types of HSP. This evidence includes the known functional role of KIF5A, a gene that I have identified as being involved in HSP, and preliminary experimental data that I have generated that implicate spastin and spartin in intracellular membrane traffic events and suggest a possible functional relationship between them. This proposal focuses on spastin and spartin and its aims are to test the hypothesis that the two proteins are functionally related components of an intracellular membrane traffic pathway that is disrupted when they are mutated. I will test this hypothesis by: a) examining whether the tissue and sub-cellular expression patterns of spastin and spartin overlap, b) further investigating preliminary experimental data that suggest physical interactions between spastin, spartin, and 2 other proteins, CHMP1.5 and gp25L2, that I identified in a yeast two-hybrid screen using spastin as bait, and which are known to be involved in intracellular membrane traffic events, c) examining in cultured mammalian cells whether knocking down expression of spastin or spartin, controlled expression of wild-type spastin or spartin, or controlled expression of mutant forms of spastin or spartin, results in any morphological or functional abnormality of intracellular membrane traffic pathways or components.

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Grant Details

Amount Awarded 180069
Applicant Surname Reid
Approval Committee Neurosciences And Mental Health
Award Date 2006-04-03T00:00:00+00:00
Financial Year 2005/06
Grant Programme: Title Intermediate Clinical Fellowship
Internal ID 073483/Z/03/A
Lead Applicant Dr Evan Reid
Partnership Value 180069
Planned Dates: End Date 2008-05-31T00:00:00+00:00
Planned Dates: Start Date 2007-06-01T00:00:00+00:00
Recipient Org: Country United Kingdom
Region East of England
Sponsor(s) Prof J. Paul Luzio