• neurodegenerative disease

This report describes Drosophila models of neurological and neurodegenerative disease using alleles of the fly gene Khc, which encodes a kinesin heavy chain. There are three highly related genes in human, KIF5A, KIF5B and KIF5C. KIF5A is implicated in multiple neurodegenerative diseases (see MIM:6028210), including spastic paraplegia 10 (FBhh0000037), neonatal myoclonus, and susceptibility to ALS (ALS25, FBhh0001470); KIF5B is not known to be implicated in disease; KIF5C is implicated in cortical dysplasia (MIM:615282). There are additional members of the kinesin heavy chain family in both species. Multiple genetic reagents, including classical amorphic and loss-of-function alleles, RNAi-targeting constructs, and alleles caused by insertional mutagenesis, have been generated for Dmel\Khc.

Of the three human KIF5 genes, Hsap\KIF5A and Hsap\KIF5B have been introduced into flies. A variant of KIF5A that is implicated in ALS25 (FBhh0001470) has been characterized; see the 'Disease-Implicated Variants' table below.

Animals homozygous for amorphic alleles of Dmel\Khc typically die during embryogenesis; less severe mutations survive to later stages, allowing characterization of locomotor and neuroanatomy defects. Larvae exhibit progressive distal paralysis; weaker mutations result in a tail-flipping phenotype that is easily scored. Several variant(s) implicated in human disease have been tested as the analogous mutation in fly Khc gene; these include a Khc mutation analogous to a variant of KIF5A that is implicated in spastic paraplegia 10 (see FBhh0000037), and a Khc mutation analogous to a newly described variant of KIF5C implicated in a neurological disorder with infantile onset epilepsy and psychomotor retardation (similar to MIM:615282). See the 'Disease-Implicated Variants' table below.

[updated May 2024 by FlyBase; FBrf0222196]