RESEARCH: Mutant Spastin disrupts axonal transport

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Hereditary spastic paraparesis: disrupted

intracellular transport associated with spastin

mutation.

McDermott CJ, Grierson AJ, Wood JD, Bingley M, Wharton

SB, Bushby KM, Shaw PJ.

Academic Neurology Unit, University of Sheffield,

Beech Hill Road, Sheffield S10 2RX, United Kingdom.

christopher.mcdermott@...

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.

SOURCE: Ann Neurol. 2003 Dec;54(6):748-59.

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