KIF2A deficiency causes early-onset neurodegeneration

KIF2A is an atypical kinesin that has the capacity to depolymerize microtubules. Patients carrying mutations in KIF2A suffer from progressive microcephaly and mental disabilities. While the role of this protein is well documented in neuronal migration, the relationship between its dysfunction and th...

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Published inProceedings of the National Academy of Sciences - PNAS Vol. 119; no. 46; p. e2209714119
Main Authors Ruiz-Reig, Nuria, Chehade, Georges, Hakanen, Janne, Aittaleb, Mohamed, Wierda, Keimpe, De Wit, Joris, Nguyen, Laurent, Gailly, Philippe, Tissir, Fadel
Format Journal Article
LanguageEnglish
Published United States National Academy of Sciences 15.11.2022
Subjects
Age
Animals
Axonal transport
Axonogenesis
Biological Sciences
Brain
Brain Diseases - metabolism
Cell migration
Depolymerization
Disabilities
Disorders
Kinesin
Kinesins - genetics
Maturation
Mice
Microencephaly
Microtubules
Microtubules - metabolism
Mutation
Neural networks
Neural stem cells
Neurodegeneration
Neurogenesis
Neurons
Neurons - metabolism
Polarity
Repressor Proteins - metabolism
Synaptogenesis
brain wiring
neurodegeneration
neuronal polarity
neurodevelopment
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Summary:KIF2A is an atypical kinesin that has the capacity to depolymerize microtubules. Patients carrying mutations in KIF2A suffer from progressive microcephaly and mental disabilities. While the role of this protein is well documented in neuronal migration, the relationship between its dysfunction and the pathobiology of brain disorders is unclear. Here, we report that KIF2A is dispensable for embryogenic neurogenesis but critical in postnatal stages for maturation, connectivity, and maintenance of neurons. We used a conditional approach to inactivate KIF2A in cortical progenitors, nascent postmitotic neurons, and mature neurons in mice. We show that the lack of KIF2A alters microtubule dynamics and disrupts several microtubule-dependent processes, including neuronal polarity, neuritogenesis, synaptogenesis, and axonal transport. KIF2A-deficient neurons exhibit aberrant electrophysiological characteristics, neuronal connectivity, and function, leading to their loss. The role of KIF2A is not limited to development, as fully mature neurons require KIF2A for survival. Our results emphasize an additional function of KIF2A and help explain how its mutations lead to brain disorders.
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Edited by Jeremy Nathans, Johns Hopkins University School of Medicine, Baltimore, MD; received June 6, 2022; accepted October 3, 2022
Author contributions: N.R.-R., G.C., and F.T. designed research; N.R.-R., J.H., and K.W. performed research; J.H., M.A., K.W., J.D.W., L.N., P.G., and F.T. contributed new reagents/analytic tools; N.R.-R., G.C., M.A., J.D.W., L.N., P.G., and F.T. analyzed data; and N.R.-R. and F.T. wrote the paper.
ISSN:0027-8424
1091-6490
DOI:10.1073/pnas.2209714119