期刊
NEUROBIOLOGY OF DISEASE
卷 147, 期 -, 页码 -出版社
ACADEMIC PRESS INC ELSEVIER SCIENCE
DOI: 10.1016/j.nbd.2020.105164
关键词
Tyr-tubulin; Dopa-tubulin; L-dopa incorporation; Parkinson's disease; L-dopa treatment, microtubules, mitochondria traffic
资金
- Agencia Nacional de Promocion Cientifica y Tecnologica de la Secretaria de Ciencia y Tecnologia del Ministerio de Cultura y Educacion [Prestamo BID-PICT 0563]
- Consejo Nacional de Investigaciones Cientificas y Tecnicas (CONICET)
- Secretaria de Ciencia y Tecnica de la Universidad Nacional de Cordoba
The study found that L-dopa irreversibly incorporates into tubulin, alters mitochondrial transport along axons, and reduces the affinity of the molecular motor KIF5B for Dopatubulin-containing microtubules. This disruption in microtubule functioning impairs mitochondrial traffic, which may have implications for Parkinson's disease patients receiving chronic L-dopa treatment.
L-dopa is the most effective drug used to date for management of Parkinson's disease symptoms. Unfortunately, long-term administration of L-dopa often results in development of motor disorders, including dyskinesias. Despite extensive research on L-dopa-induced dyskinesia, its pathogenesis remains poorly understood. We demonstrated previously that L-dopa can be post-translationally incorporated into the C-terminus of alpha-tubulin in living cells. In the present study, we investigated the effect of the presence of L-dopa-tubulin-enriched microtubules on mitochondrial traffic mediated by molecular motor KIF5B. Using biochemical approaches in combination with experiments on neuronal cell lines and mouse hippocampal primary cultures, we demonstrated that L-dopa incorporation into tubulin is irreversible. Transport of mitochondria along the axon was altered after L-dopa treatment of cells. In L-dopa-treated cells, mitochondria had reduced ability to reach the distal segment of the axon, spent more time in pause, and showed reduced velocity of anterograde movement. KIF5B motor, a member of the kinesin family involved in mitochondrial transport in neurons, showed reduced affinity for Dopatubulin-containing microtubules. Our findings, taken together, suggest that tyrosination state of tubulin (and microtubules) is altered by L-dopa incorporation into tubulin; the gradual increase in amount of altered microtubules affects microtubule functioning, impairs mitochondrial traffic and distribution, and this could be relevant in Parkinson's disease patients chronically treated with L-dopa.
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