Conventional kinesin is composed of heavy chains (kinesin-1, in red) and light chains (KLCs, in blue) homodimers (DeBoer et al., 2008). Kinesin-1s use energy derived from ATP hydrolysis to translocate along microtubules (MT). KLCs play a critical role in the binding of conventional kinesin to transported membrane-bounded organelle (MBO) cargoes (Stenoien and Brady, 1997). Recent studies identified various protein kinases, which directly phosphorylate selected subunits of conventional kinesin. The functional consequence of each phosphorylation event is determined in part by the major function of the subunit targeted. For example, phosphorylation of KLCs by GSK3 (Morfini et al., 2002a) and CK2 (Morfini et al., 2001; Pigino et al., 2009) promotes the detachment of conventional kinesin from membranes, whereas phosphorylation of kinesin-1s by JNK inhibits the binding of conventional kinesin to microtubules (Morfini et al., 2006; Morfini et al., 2009). Similar regulatory mechanisms have been proposed for cytoplasmic dynein (Susalka and Pfister, 2000; Morfini et al., 2007c). These findings provide a molecular basis for the delivery of selected motor cargoes at specialized axonal compartments (Morfini et al., 2001). The heterogeneity of MBO cargoes suggests the involvement of additional kinases in the regulation of molecular motors.

A) Healthy neurons: The canonical full-length isoform can fold into the “paper clip” conformation, which masks the toxic N-terminal region (red). FAT is unaffected by soluble monomeric full-length tau. B) Neuronal dysfunction: Polymers of canonical tau form, which leads to an unmaking of the toxic region. The truncated non-canonical 6D/6P tau monomers (also schematically depicted) cannot fold and presents an unmasked toxic region constitutively. Exposure of the toxic region in tau isoforms activates a PP1-GSK cascade. This results in phosphorylation of KLCs (blue), dissociation of the cargo (gray sphere), and FAT inhibition. C) Neuron survival: During NFT formation, modifications (e.g. truncation and phosphorylation) of tau in the polymers vie for preeminence in the neuron. If modified NFT formation predominates, FAT remains relatively unaffected and the cell likely survives for some years.

In this model, polyQ expansion of polypeptides directly or indirectly leads to activation of one or more MAPKKK, which in turn activate one or more MAPKK, finally activating JNK1 and JNK3. Increased JNK1/JNK3 activity represents a toxic gain of function common to several different pathogenic polyQ-expanded polypeptides (Morfini et al., 2006; Morfini et al., 2009). Altered folding of the pathogenic protein may lead to aggregate formation and/or altered association with binding partners could contribute to disease-specific characteristics for each polyQ disease (Morfini et al., 2005). The role of aggregates in this model remains unknown. Different consequences are associated with increased activation of each JNK isoform. Both ubiquitous JNK1 and neuron-specific JNK3 can alter gene expression in neurons (Sugars and Rubinsztein, 2003), but only JNK3 inhibits FAT (Morfini et al., 2009). Reductions in FAT lead to failure of neurotransmission and degeneration of the distal axon. When the extent of synaptic failure passes a critical threshold, cell death pathways are triggered in the neuronal cell body and apoptosis ensues.

A. Schematic summarizing the changes that occur in axons in the Plp1 null mouse model of spastic paraplegia type 2. Despite almost normal myelination, axonal organelles accumulate at the distal juxtaparanodal regions of myelinated axons, eventually causing localized swelling of the axon. Axonal swellings are not preferentially localized to proximal or distal portions of an axon and it is likely (though not confirmed) that a single axon contains multiple swellings. The distal portions of the long axons of the spinal cord eventually degenerate (represented by the dashed line). B-E. Electron micrographs of CNS fiber changes. Organelle accumulation and cytoskeletal disruption in a myelinated axon from a P120 Plp1 null mouse spinal cord (B). Morphologically similar organelle accumulations in the spinal cord (C) and optic nerve (D) of P120 Cnp1 null mice. Swelling of the inner tongue process of the oligodendrocyte (asterisks in D and E) is a feature of the Cnp1 null mouse. The swollen tongue appears not to compress the axon, but seems to be accommodated by expansion of the compact myelin sheath, as illustrated in these P120 optic nerve fibres. Scale bars: B & C 2 μm, D & E 1 μm.

Certain toxic chemicals, like MPTP and its metabolite MPP+ can produce a severe parkinsonism, but the pathogenic process was poorly understood. Agents like MPP+, rotenone and paraquat are thought to act at the level of mitochondria, but mitochondria are ubiquitous and the neurodegenerative parkinsonian phenotype is highly selective (Dauer and Przedborski, 2003). In isolated axons, MPP+ activates caspase 3, which cleaves and activates a specific isoform of protein kinase C, PKCδ. Activated PKCδ then phosphorylate dynein intermediate chains and activate retrograde FAT. Further, activation of PKCδ reduces anterograde FAT. These imbalances in FAT result in depletion of synaptic vesicles from synapses, failure of neurotransmission (Morfini et al., 2007c; Serulle et al., 2007), altered trophic factor support (Delcroix et al., 2004). These events ultimately would lead to neuronal cell death.

Several protein kinases have been identified which phosphorylate and regulate specific functional activities of conventional kinesin and cytoplasmic dynein, the major microtubule-dependent motor proteins responsible for FAT. Significantly, various unrelated neuropathogenic proteins induce alterations in FAT through independent mechanism involving the activation of specific kinases and phosphorylation of selected molecular motor subunits. The complexity of FAT regulation suggests the existence of additional pathogenic pathways. Inhibitory events are indicated by T-shaped lines; arrowheads indicate activation. Tau Fil: Filamentous Tau, PS1: presenilin-1, SOD1: superoxide dismutase 1, Htt: Huntingtin, A.R.: Androgen Receptor, oA β: oligomeric amyloid β, α -Syn: α -synuclein.