Kinase-Based Regulation of Fast Axonal Transport in Disease and Health

Neurons are highly polarized cells with distinct subcellular compartments such as the soma, dendrites and axons. The lack of axonal protein synthesis and long distances between the neuronal soma and discrete axonal compartments impose a unique challenge on neurons. Therefore, delivery of molecular cargoes by conventional kinesin (kinesin) and cytoplasmic dynein (CDyn), a process referred to as fast axonal transport (FAT), is essential for the survival and functions of neurons. The microtubule-based motor proteins kinesin and CDyn exist as phosphoproteins, and phosphorylation of their subunits can alter their functions, indicating that FAT can be regulated by phosphorylation of kinesin and CDyn. Dysregulated activation of select kinases and subsequent phosphorylation of motor protein subunits lead to FAT defects in neurodegenerative diseases. For instance, aberrant activation of c-Jun amino-terminal kinase 3 (JNK3) in Huntington's disease (HD) results in FAT defects by phosphorylation of kinesin heavy chain which leads to inhibition its microtubule-binding activity. In order to examine the contribution of JNK3 in HD pathology, we crossed a mouse model of HD, R6/2 mouse, with a JNK3 knockout mouse (JNK3-/-) to generate R6/2-JNK3-/- mice. R6/2-JNK3-/- mice showed significant amelioration of HD pathology in R6/2 mice and improved their survival, indicating that preventing FAT defects by inhibition of JNK3 is a promising therapeutic intervention for HD. On the other hand, we identified a novel kinase pathway involving activation of tyrosine receptor kinase B (TrkB), Src family kinases (SFKs), and protein kinase D1 (PKD1) leads to phosphorylation of CDyn upon neurotrophin signaling and activate retrograde FAT of signaling endosomes. These results demonstrate that FAT can be regulated by phosphorylation of kinesin and CDyn in both pathological and non-pathological conditions, and inhibition of select kinases mediating the FAT inhibition in neurodegenerative diseases is a promising therapeutic strategy.