Acta Neuropathologica Communications · 2019 · 26 citations · 42 references
Life SciencesMolecular BiologyNeurobiologyMolecular Cell BiologyMolecular NeurobiologyMolecular NeuroscienceMolecular Basis Of NeurodegenerationNeurodegeneration MechanismsNeurodegenerative DiseasesNeurodegenerative DisordersProtein Kinase CascadesProtein Trafficking In NeuronsAlzheimer Disease DementiaAnterograde Axonal TransportAxonal Transport DefectsAxonal Transport ImpairmentAxonal Transport PathwaysCyclin-dependent Kinase SubunitsKinesin-mediated TransportNeurodegenerative Disease Mechanisms
Cyclin dependent kinase-5 (cdk5)/p35 is a neuronal kinase that regulates key axonal and synaptic functions but the mechanisms by which it is transported to these locations are unknown. Lemur tyrosine kinase-2 (LMTK2) is a binding partner for p35 and here we show that LMTK2 also interacts with kinesin-1 light chains (KLC1/2). Binding to KLC1/2 involves a C-terminal tryptophan/aspartate (WD) motif in LMTK2 and the tetratricopeptide repeat (TPR) domains in KLC1/2, and this interaction facilitates axonal transport of LMTK2. Thus, siRNA loss of KLC1 or mutation of the WD motif disrupts axonal transport of LMTK2. We also show that LMTK2 facilitates the formation of a complex containing KLC1 and p35 and that siRNA loss of LMTK2 disrupts axonal transport of both p35 and cdk5. Finally, we show that LMTK2 levels are reduced in Alzheimer's disease brains. Damage to axonal transport and altered cdk5/p35 are pathogenic features of Alzheimer's disease. Thus, LMTK2 binds to KLC1 to direct axonal transport of p35 and its loss may contribute to Alzheimer's disease.
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p35 is a neural-specific regulatory subunit of cyclin-dependent kinase 5
Li‐Huei Tsai, Ivana Delalle, Verne S. Caviness et al. · Nature · 1994 · 923 citations
A brain-specific activator of cyclin-dependent kinase 5
John I. Lew, Qi-Quan Huang, Robert J. Winkfein et al. · Nature · 1994 · 581 citations