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

Lina Wang,Anthony Brown

doi:10.1186/1750-1326-5-52

Abstract

BackgroundHereditary spastic paraplegias are a group of neurological disorders characterized by progressive distal degeneration of the longest ascending and descending axons in the spinal cord, leading to lower limb spasticity and weakness. One of the dominantly inherited forms of this disease (spastic gait type 10, or SPG10) is caused by point mutations in kinesin-1A (also known as KIF5A), which is thought to be an anterograde motor for neurofilaments.ResultsWe investigated the effect of an SPG10 mutation in kinesin-1A (N256S-kinesin-1A) on neurofilament transport in cultured mouse cortical neurons using live-cell fluorescent imaging. N256S-kinesin-1A decreased both anterograde and retrograde neurofilament transport flux by decreasing the frequency of anterograde and retrograde movements. Anterograde velocity was not affected, whereas retrograde velocity actually increased.ConclusionsThese data reveal subtle complexities to the functional interdependence of the anterograde and retrograde neurofilament motors and they also raise the possibility that anterograde and retrograde neurofilament transport may be disrupted in patients with SPG10.

Highlights

Hereditary spastic paraplegias are a group of neurological disorders characterized by progressive distal degeneration of the longest ascending and descending axons in the spinal cord, leading to lower limb spasticity and weakness
Since kinesin-1A appears to be a motor for neurofilaments, we have investigated the effect of an SPG10 mutation in this motor on neurofilament transport in cultured neurons
We show that expression of N256S-kinesin1A disrupts both anterograde and retrograde neurofilament neurofilament transport in cultured mouse cortical neurons, raising the possibility that neurofilament transport may be disrupted in patients with SPG10

Summary

Introduction

Hereditary spastic paraplegias are a group of neurological disorders characterized by progressive distal degeneration of the longest ascending and descending axons in the spinal cord, leading to lower limb spasticity and weakness. One of the dominantly inherited forms of this disease (spastic gait type 10, or SPG10) is caused by point mutations in kinesin-1A ( known as KIF5A), which is thought to be an anterograde motor for neurofilaments. Hereditary spastic paraplegias are a group of neurological disorders characterized by progressively increasing lower-extremity weakness and spasticity [1]. The primary cause appears to be distal degeneration of the longest ascending and descending axons in the spinal cord, though the explanation for this selective vulnerability is not known. One of the autosomal dominant forms, SPG10, is caused by mutations in kinesin-1A, known as KIF5A, which is a member of the kinesin-1 family of motor proteins. Little is known about the cargoes of kinesin-1A, though potential cargoes and interactors include HAP-1 (huntingtin associated protein-1) [8], DISC-1 (disrupted in schizophrenia protein-1) and the NUDEL/LIS1/14-3-3ε complex [9], Grb (growth factor receptor bound protein-2) [10], and b-dystrobrevin [11,12]

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