44th FEBS Congress, Krakow, Poland, 6 - 11 July 2019, pp.2-18
Spinal muscular atrophy (SMA) is a neurodegenerative disease, causing degeneration of alpha motor neurons of the spinal cord and progressive muscle atrophy.
Mutations of Survival of motor neuron 1 (SMN1) gene lead to the absence of the ubiquitouslyexpressed SMN protein in all cells, however, motor neurons are
particularly sensitive to SMN loss. Previous reports indicated that SMN is involved in the maintanence of cytoskeleton integrity and SMNdeficiency causes
dysregulations of proteins related to cytoskeleton organization in neurons. We found that microtubuleassociated protein 1B (MAP1B) is significantly upregulated in
both in vitro and in vivo SMA models. Considering a regulatory role of MAP1B on microtubule stability, we knockeddown SMN in motor neuronlike NSC34 cells
and treated with nocodazole, a depolymerization agent. Immunofluorescence analysis showed increased neurite fragmentation in SMNdeficient cells compared to
controls in response to nocodazole. Additionally, we analyzed microtubule stability markers and found a significant downregulation of detyrosinated alpha tubulin levels
in SMN knockdown cells by Western blot. Reduced alpha tubulin detyrosination is associated with an increased levels of tubulin tyrosine ligase (TTL), a MAP1Binteracting protein. MAP1B knockdown restored both TTL and alpha tubulin detyrosination levels and also ameliorated defective mitochondrial distribution in SMNdepleted cells. Our results suggest that MAP1B upregulation alters TTL activity which results in reduced microtubule stability in the absence of SMN. Our findings will
help to gain a better understanding about impaired cytoskeletal networks in SMA pathomechanisms. This study was funded by The Scientific and Technological
Research Council of Turkey (TUBİTAK, Project number; 216S770).