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

PLoS Genet. 2020 Nov 02;16(11):e1009104. eCollection 2020 Nov
Ines Leca 1 , Alexander William Phillips 1 , Iris Hofer 1 , Lukas Landler 2 , Lyubov Ushakova 1 , Thomas David Cushion 1 , Gerhard Dürnberger 3 , Karel Stejskal 3 , Karl Mechtler 3 , David Anthony Keays 4
Ines Leca 1 , Alexander William Phillips 1 , Iris Hofer 1 , Lukas Landler 2 , Lyubov Ushakova 1 , Thomas David Cushion 1 , Gerhard Dürnberger 3 , Karel Stejskal 3 , Karl Mechtler 3 , David Anthony Keays 4
+ et al

[No authors listed]

Author information
  • 1 Research Institute of Molecular Pathology (IMP), Vienna Biocenter (VBC), Vienna, Austria.
  • 2 Institute of Zoology, University of Natural Resources and Life Sciences (BOKU), Vienna, Austria.
  • 3 Institute of Molecular Biotechnology of the Austrian Academy of Sciences (IMBA), Vienna Biocenter (VBC), Vienna, Austria.
  • 4 Division of Neurobiology, Department Biology II, Ludwig-Maximilians-University Munich, Planegg-Martinsried 82152, Germany.

摘要


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.