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

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.

The KIF1A homolog Unc-104 is important for spontaneous release, postsynaptic density maturation and perisynaptic scaffold organization

“…Similar with a previously described HSP Type 10 (SPG10) Drosophila model, larval locomotion was also severely impaired in unc-104 bris mutant larvae2052. However, while robust structural defects were observed upon disturbance of Kinesin-1 based transport52, no signs of synapse dismantling were observed in unc-104 bris mutant larvae20.…”

“…However, while robust structural defects were observed upon disturbance of Kinesin-1 based transport52, no signs of synapse dismantling were observed in unc-104 bris mutant larvae20. Therefore it is more likely that the observed reduction of SSR associated proteins (Fig.…”

Disruption of Axonal Transport Perturbs Bone Morphogenetic Protein (BMP) - Signaling and Contributes to Synaptic Abnormalities in Two Neurodegenerative Diseases

“…Mutations in Atlastin-1, another HSP gene, exhibited a dominant-negative effect on the trafficking of BMPRII (wit), disrupting BMP signaling [86]. Intriguingly, these HSP gene mutants also exhibited axonal transport defects [43], [86], [87], suggesting that perturbations in long distant transport likely is a common mechanism in HSP disease pathology. Increased levels of BMP6 have also been observed in AD brains and in transgenic AD mice together with impaired neurogenesis [93].…”

Extended phenotypic spectrum of KIF5A mutations

“…The results support a loss of endogenous kinesin-1 function due to a selective dominant-negative mechanism of action on the kinesin complexes, rather than a gain of toxicity. 15,19 Only mutations located in the motor domain changed the kinesin gliding properties but the mutation in the neck (A361V) did not. This suggests that mutations outside of the motor domain may have a different disease mechanism.…”