One gene, many phenotypes: the role of KIF5A in neurodegenerative and neurodevelopmental diseases

Abstract

Kinesin family member 5 A (KIF5A) is a neuron-specific molecular motor involved in anterograde transport. KIF5A mediates a wide range of trafficking processes that are only partially shared with the other members of the KIF5 family. Since 2002, several disease-causing mutations have been found in the KIF5A gene and a link between the specific domain in the encoded protein affected by mutations and the associated phenotype has become evident. Point mutations targeting KIF5A motor and stalk domains, that are expected to impair KIF5A motility, mainly associate with spastic paraplegia type 10 (SPG10) and axonal Charcot-Marie-Tooth (CMT) disease. Oppositely, translational frameshifts causing the elongation of KIF5A tail enhance KIF5A migration towards cell periphery, induce kinesin aggregation, and are linked to amyotrophic lateral sclerosis (ALS) or neonatal intractable myoclonus (NEIMY). This review correlates KIF5A structure and roles in neuronal trafficking with its involvement in the above-mentioned neurodegenerative and neurodevelopmental conditions.

Supplementary Information: The online version contains supplementary material available at 10.1186/s12964-025-02277-x.

Keywords: Amyotrophic lateral sclerosis; Charcot-Marie-Tooth disease; Hereditary spastic paraplegia; KIF5A; Neonatal intractable myoclonus.

Fig. 1

Comparison of KIF5A, KIF5B, and KIF5C protein structures divided into the three main functional domains of conventional kinesins (motor, stalk, and tail domains). The three KIF5 isoforms are highly similar, but KIF5A has the longest tail domain, with 73 unique amino acids in its C-terminal region, making it capable to uniquely bind to specific cargoes

Fig. 2

KIF5A is involved in the anterograde transport of cytoskeletal proteins (e.g. neurofilament), RNA granules (e.g. SFPQ-containing ribonucleoprotein granules), vesicles (e.g. neurotransmitter receptor carriers), and organelles (e.g. mitochondria and lysosomes) along microtubules in either axons or dendrites

Fig. 3

Distribution of KIF5A pathogenic variants associated with HSP/SPG10 (black), CMT (brown), ALS (red), NEIMY (orange), or other phenotypes (pink). Variants associated with more than one disease are in grey. See the Supplementary Table for further details. Adapted from Cozzi M, Magri S et al. Altered molecular and cellular mechanisms in KIF5A-associated neurodegenerative or neurodevelopmental disorders. Cell Death Dis 2024; 15: 692 [83].

Fig. 4

Schematic representation of the main molecular mechanisms underpinning KIF5A-linked neurodegenerative and neurodevelopmental diseases depending on the affected protein domain. Adapted from Cozzi M, Magri S et al. Altered molecular and cellular mechanisms in KIF5A-associated neurodegenerative or neurodevelopmental disorders. Cell Death Dis 2024; 15: 692 [83].