Mutant spastin proteins promote deficits in axonal transport through an isoform-specific mechanism involving casein kinase 2 activation

LEO, LANFRANCO; WEISSMANN, CARINA (COPRIMER AUTOR); BURNS, MATTHEW; KANG, MINSU; SONG, YUYU; QIANG, LIANG; BRADY, SCOTT T.; BAAS, PETER W.; MORFINI, GERARDO

HUMAN MOLECULAR GENETICS

OXFORD UNIV PRESS

Año: 2017

0964-6906

Mutations of various genes cause hereditary spastic paraplegia (HSP), a neurological diseaseinvolving dying-back degeneration of upper motor neurons. From these, mutations in the SPASTgene encoding the microtubule-severing protein spastin account for most HSP cases.Cumulative genetic and experimental evidence suggests that alterations in various intracellulartrafficking events, including fast axonal transport (FAT), may contribute to HSP pathogenesis.However, mechanisms linking SPAST mutations to such deficits remain largely unknown.Experiments presented here using isolated squid axoplasm reveal inhibition of FAT as acommon toxic effect elicited by spastin proteins with different HSP mutations, independent ofmicrotubule-binding or severing activity. Mutant spastin proteins produce this toxic effect onlywhen presented as the tissue-specific M1 isoform, not when presented as the ubiquitouslyexpressedshorter M87 isoform. Biochemical and pharmacological experiments further indicatethat the toxic effects of mutant M1 spastins on FAT involve casein kinase 2 (CK2) activation. Inmammalian cells, expression of mutant M1 spastins, but not their mutant M87 counterparts,promotes abnormalities in the distribution of intracellular organelles that are correctable bypharmacological CK2 inhibition. Collectively, these results demonstrate isoform-specific toxiceffects of mutant M1 spastin on FAT, and identify CK2 as a critical mediator of these effects