Physiological axonal transport is fundamental for maintaining the complex neuronal homeostasis. Neurons are polarised cells with majority of their proteins synthetized in the soma and require therefore well-organized intracellular transport to reach their targets. There are four vital actors in this play: microtubule tracks, molecular motor proteins, cargoes and energy in the form of ATP. Any disruption to this precise machinery perturbs axonal transport and causes aberrant accumulation of proteins, and organelles in different neurodegenerative pathologies in dementias, movement disorders and motor neuron diseases, for review see [
52].
Kinesin-1 is a major molecular motor protein mediating axonal transport of several key cargoes such as mitochondria, amyloid precursor protein and synaptic vesicle precursors towards synapses [
61‐
64]. Most functional kinesin-1 is a heterotetramer composed of two kinesin-1 heavy chains and two kinesin-1 light chains (KLCs). Kinesin-1 heavy chains move along microtubules while KLCs are mainly involved in cargo binding [
62]. Phosphorylation of KLCs is an important cargo binding and releasing regulatory mechanism [
61,
65,
66]. GSK3β can directly phosphorylate KLC2 to induce cargo release and supress kinesin-1 mediated transport [
13,
65]. Involvement of CDK5 in GSK3β-dependent regulation of axonal transport was first described by Morfini et al. [
66]. They have reported that CDK5 indirectly regulates GSK3β activity via PP1C. However, the nature of interaction (i.e. direct or indirect) between CDK5/p35 and PP1C was unclear [
66]. Manser and co-workers have recently revealed that LMTK2 is the missing link between CDK5/p35, PP1C and GSK3β which brings these proteins together in one phosphorylation pathway to regulate kinesin-1 based axonal transport [
13,
15]. In this novel signalling pathway, CDK5/p35 activates LMTK2 by phosphorylating it at serine-1418. Phosphorylated LMTK2 in turn reduces PP1C activity by phosphorylating it at threonine-320. Finally, phosphorylation of PP1C threonine-320 leads to increased inhibitory phosphorylation of GSK3β at serine-9 [
13,
15]. Inhibited GSK3β is not able to phosphorylate KLC2 which promotes KLC2 binding to cargos, such as mothers against decapentaplegic homolog 2 (Smad2). Thus, LMTK2 is a negative regulator of KLC2 phosphorylation and LMTK2 activity promotes kinesin-1 based transport of Smad2 [
13,
67]. Smad2 is a transcription factor which shuttles between the cytoplasm and nucleus, and is a crucial player in transforming growth factor-β (TGFβ) signalling pathway [
68]. TGFβ induces Smad2 translocation into the nucleus where it regulates the expression of TGFβ-responsive genes [
69]. siRNA knockdown of LMTK2 disrupts Smad2 binding to KLC2 and importantly, it also inhibits TGFβ-induced nuclear signalling of Smad2 probably due to affected Smad2 transport [
13]. Reduced
LTMK2 gene-expression has been detected in an Alzheimer’s disease tau mouse model [
54]. Additionally, altered TGFβ/Smad2 signalling has been observed in common neurodegenerative diseases, including Alzheimer’s disease [
70,
71] suggesting that LMTK2 is not only involved in the regulation of kinesin-1 based transport but also can contribute the pathomechanism of neurodegenerative diseases by affecting axonal transport.