Axonal transport in motor neuron diseases: The role of KIF5A

A growing number of studies are currently focusing on axonal transport defects as a common nominator in neurodegeneration. KIF5A, a major component of the axonal transport machinery, has been associated with MNDs, including Amyotrophic Lateral Sclerosis and Hereditary Spastic Paraplegia. The role of KIF5A in SMA and specifically in mitochondrial transport via the KIF5A/TRAKs/Miro1 complex, to our knowledge, has not been studied yet. Our study aims to investigate the potential implication of Kif5a and Miro1 in a SMA mouse model and identify a therapeutic intervention. Also, we attempt to identify a potential interaction of KIF5A with SMN and to better characterise two C-terminal mutations in KIF5A causing ALS and HSP. Our results show a differential expression of Kif5a and Miro1 in different brain regions and consistently lower Kif5a and Miro1 levels in the spinal cord of SMNΔ7 mice during the course of the disease. We report significantly upregulated levels of mir-140-3p in the spinal cord of SMA mice and identify miR-140-3p as a regulator of Kif5a expression. Finally, we provide preliminary data suggesting a KIF5A-SMN interaction in motor neurons and a loss of TRAK1 binding with KIF5A in the case of the HSP mutation. The results are suggestive of the implication of Kif5a and Miro1 in the anterograde transport defects observed in SMA mice, consistent with previous studies in ALS. MiR-140-3p could potentially restore Kif5a levels and the axonal transport deficits in SMA. Future in-vivo studies are required to assess the effects of mir-140-3p in SMA and to confirm SMN as a novel KIF5A cargo. Also, we suggest that the HSP mutation potentially has a different pathogenic mechanism, in regards to TRAK1 binding, to the ALS mutations. Overall, with this thesis we report the first association of Kif5a and Miro1 in SMA pathogenesis and we suggest that KIF5A-elevating strategies could be beneficial to SMA and potentially other MNDs