Table 1.
Potential impact of MND-associated genes on the axonal transport pathway. Pathogenic variants of the proteins in this table have been linked to disrupted axonal transport.
| Gene | Protein | Potential consequence of mutation on axonal transport | Disease |
|---|---|---|---|
| ALS2 | Alsin | Impaired endocytic trafficking, signalling endosomes | FALS (ALS2) |
| C9orf72 | C9orf72 | Defective transport of mitochondria | FALS (ALS-FTD1); SALS; FTD |
| CHMP2B | Charged multivesicular body protein 2B | Impaired endocytic trafficking, signalling endosomes | FALS (ALS17); SALS; FTD |
| DCTN1 | Dynactin 1 (p150, glued homolog, Drosophila) | Altered axonal transport and vesicle trafficking, impaired signalling endosome trafficking | FALS; SALS; HMN7B; PMA; PSP; Perry syndrome |
| FUS | RNA-binding protein FUS | Defective transport of mitochondria, aberrant microtubule acetylation | FALS (ALS6); SALS |
| SPG11 | Spatacsin | Axonal destabilisation, reduced tubulin acetylation, reduced anterograde vesicle transport | FALS (ALS5); HSP (SPG11) |
| SOD1 | Superoxide dismutase 1 | Impaired transport of mitochondria, microtubule stability, modulation of motor proteins via p38 MAP kinase | FALS (ALS1); SALS |
| TARDBP | TAR DNA-binding protein 43 | Defective transport of mitochondria and mRNP granules; reduced expression of dynactin 1; aberrant microtubule stability/acetylation, | FALS (ALS10); SALS |
| TUBA4A | Tubulin, alpha 4a | Destabilisation of microtubules, general transport defect? | FALS |
| VAPB | Vesicle-associated membrane protein-associated protein B | Impaired transport of mitochondria and vesicles | FALS (ALS8); SMA; PMA |
| KIF1A | Kinesin Family Member 1A | Reduced kinesin-3 mediated transport | HSP (SPG30) |
| KIF5A | Kinesin heavy chain | Reduced kinesin-1 mediated transport, impaired neurofilament transport | HSP (SPG10) |
| SPAST | Spastin | Destabilisation of microtubules, impaired transport of mitochondria and vesicles | HSP (SPG4) |
| AR | Androgen receptor | Defective retrograde and anterograde transport, modulation of motor proteins via JNK | SBMA |
Abbreviations: FALS, familial ALS; SALS, sporadic ALS; SMA, spinal muscular atrophy; SBMA, spinal and bulbar muscular atrophy; PMA, progressive muscular atrophy; FTD, frontotemporal dementia.
(Ref: http://alsod.iop.kcl.ac.uk/home.aspx;Abel et al., 2012; this review.)