title: Hereditary spastic paraparesis: disrupted intracellular transport associated with spastin mutation.
abstract: The commonest cause of hereditary spastic paraplegia (HSP) is mutation in the spastin gene. Both the normal function of spastin in the central nervous system and the mechanism by which mutation in spastin causes axonal degeneration are unknown. One hypothesis is that mutant spastin disrupts microtubule dynamics, causing an impairment of organelle transport on the microtubule network, which leads to degeneration in the distal parts of long axons. To study this neuronal and non-neuronal cells were transfected with either wild type or mutant spastin proteins. We demonstrated evidence of a transient interaction of wild-type spastin with microtubules, with resulting disassembly of microtubules, supporting a role for wild-type spastin as a microtubule-severing protein. Mutant spastin demonstrated an abnormal interaction with microtubules, colocalizing with but no longer severing microtubules. The abnormal interaction of mutant spastin with microtubules was demonstrated to be associated with an abnormal perinuclear clustering of mitochondria and peroxisomes, suggestive of an impairment of kinesin-mediated intracellular transport. Our findings indicate that an abnormal interaction of mutant spastin with microtubules, which disrupts organelle transport on the microtubule cytoskeleton, is likely to be the primary disease mechanism in HSP caused by missense mutations in the spastin gene.
authors.affiliation: Academic Neurology Unit, University of Sheffield, Beech Hill Road, Sheffield S10 2RX, United Kingdom. christopher.mcdermott@sth.nhs.uk
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: McDermott
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Grierson
authors.forename: Jonathan D
authors.initials: JD
authors.lastname: Wood
authors.forename: Megan
authors.initials: M
authors.lastname: Bingley
authors.forename: Stephen B
authors.initials: SB
authors.lastname: Wharton
authors.forename: Katharine M D
authors.initials: KM
authors.lastname: Bushby
authors.forename: Pamela J
authors.initials: PJ
authors.lastname: Shaw
mesh_terms: D000251:Adenosine Triphosphatases; D001692:Biological Transport / Q000235:genetics; D002135:Calcium-Binding Proteins / Q000235:genetics*; D002460:Cell Line; D006801:Humans; D007424:Intracellular Fluid / Q000502:physiology*; D008870:Microtubules / Q000235:genetics / Q000473:pathology; D009154:Mutation / Q000235:genetics*; D009474:Neurons / Q000473:pathology; D015419:Spastic Paraplegia, Hereditary / Q000235:genetics* / Q000473:pathology; D000074181:Spastin
chemical_list: D002135:Calcium-Binding Proteins; D000251:Adenosine Triphosphatases; D000074181:Spastin; C400283:SPAST protein, human