A proteomic survey of microtubule-associated proteins in a R402H TUBA1A mutant mouse

English version

Autoři: Ines Leca ^aff001; Alexander Phillips ^aff001; Iris Hofer ^aff001; Lukas Landler ^aff001; Lyubov Ushakova ^aff001; Thomas David Cushion ^aff001; Gerhard Dürnberger ^aff001; Karel Stejskal ^aff001; Karl Mechtler ^aff001; David Anthony Keays ^aff001; Alexander William Phillips ^aff001
Působiště autorů: Research Institute of Molecular Pathology (IMP), Vienna Biocenter (VBC), Vienna, Austria ^aff001; Institute of Zoology, University of Natural Resources and Life Sciences (BOKU), Vienna, Austria ^aff002; Gregor Mendel Institute (GMI), Austrian Academy of Sciences, Vienna Biocenter (VBC), Vienna, Austria ^aff003; Institute of Molecular Biotechnology of the Austrian Academy of Sciences (IMBA), Vienna Biocenter (VBC), Vienna, Austria ^aff004; Department of Anatomy and Neuroscience, University of Melbourne, Parkville, Australia ^aff005; Division of Neurobiology, Department Biology II, Ludwig-Maximilians-University Munich, Planegg-Martinsried 82152, Germany ^aff006
Vyšlo v časopise: A proteomic survey of microtubule-associated proteins in a R402H TUBA1A mutant mouse. PLoS Genet 16(11): e32767. doi:10.1371/journal.pgen.1009104
Kategorie: Research Article
doi: https://doi.org/10.1371/journal.pgen.1009104

Souhrn

Microtubules play a critical role in multiple aspects of neurodevelopment, including the generation, migration and differentiation of neurons. A recurrent mutation (R402H) in the α-tubulin gene TUBA1A is known to cause lissencephaly with cerebellar and striatal phenotypes. Previous work has shown that this mutation does not perturb the chaperone-mediated folding of tubulin heterodimers, which are able to assemble and incorporate into the microtubule lattice. To explore the molecular mechanisms that cause the disease state we generated a new conditional mouse line that recapitulates the R402H variant. We show that heterozygous mutants present with laminar phenotypes in the cortex and hippocampus, as well as a reduction in striatal size and cerebellar abnormalities. We demonstrate that homozygous expression of the R402H allele causes neuronal death and exacerbates a cell intrinsic defect in cortical neuronal migration. Microtubule sedimentation assays coupled with quantitative mass spectrometry demonstrated that the binding and/or levels of multiple microtubule associated proteins (MAPs) are perturbed by the R402H mutation including VAPB, REEP1, EZRIN, PRNP and DYNC1l1/2. Consistent with these data we show that the R402H mutation impairs dynein-mediated transport which is associated with a decoupling of the nucleus to the microtubule organising center. Our data support a model whereby the R402H variant is able to fold and incorporate into microtubules, but acts as a gain of function by perturbing the binding of MAPs.

Klíčová slova:

Hippocampus – Homozygosity – Lysosomes – Microtubules – Motor proteins – Neurons – Tubulins – Neuron migration

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