LMTK2 binds to kinesin light chains to mediate anterograde axonal transport of cdk5/p35 and LMTK2 levels are reduced in Alzheimer's disease brains

Acta Neuropathol Commun. 2019 May 8;7(1):73. doi: 10.1186/s40478-019-0715-5.

Abstract

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.

Keywords: Alzheimer’s disease; Axonal transport; Cyclin dependent kinase-5/p35; Kinesin-1; Lemur tyrosine kinase-2.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing / metabolism*
  • Alzheimer Disease / metabolism*
  • Animals
  • Axonal Transport*
  • Brain / metabolism*
  • Cell Cycle Proteins / metabolism*
  • Cyclin-Dependent Kinase 5 / metabolism*
  • HEK293 Cells
  • Humans
  • Membrane Proteins / metabolism*
  • Microtubule-Associated Proteins / metabolism*
  • Neurons / metabolism
  • Protein Binding
  • Protein-Serine-Threonine Kinases / metabolism*
  • Rats

Substances

  • Adaptor Proteins, Signal Transducing
  • CDCA5 protein, human
  • Cell Cycle Proteins
  • Membrane Proteins
  • Microtubule-Associated Proteins
  • kinesin light-chain proteins
  • Cyclin-Dependent Kinase 5
  • LMTK2 protein, human
  • Protein-Serine-Threonine Kinases