Axonal transport defects in neurodegenerative diseases

Abstract

Adult-onset neurodegenerative diseases (AONDs) comprise a heterogeneous group of neurological disorders characterized by a progressive, age-dependent decline in neuronal function and loss of selected neuronal populations. Alterations in synaptic function and axonal connectivity represent early and critical pathogenic events in AONDs, but molecular mechanisms underlying these defects remain elusive. The large size and complex subcellular architecture of neurons render them uniquely vulnerable to alterations in axonal transport (AT). Accordingly, deficits in AT have been documented in most AONDs, suggesting a common defect acquired through different pathogenic pathways. These observations suggest that many AONDs can be categorized as dysferopathies, diseases in which alterations in AT represent a critical component in pathogenesis. Topics here address various molecular mechanisms underlying alterations in AT in several AONDs. Illumination of such mechanisms provides a framework for the development of novel therapeutic strategies aimed to prevent axonal and synaptic dysfunction in several major AONDs.

Figure 1.

Protein kinases phosphorylate and regulate conventional kinesin. Conventional kinesin is composed of heavy chain (kinesin-1, in red) and light chain (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 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., 2006b, 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.

Figure 2.

Schematic representation of tau-mediated toxicity to FAT. 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 noncanonical 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.

Figure 3.

Inhibition of FAT as a common mechanism for polyQ expansion disease pathogenesis. In this model, polyQ expansion of polypeptides directly or indirectly leads to activation of one or more MAPKKKs, which in turn activate one or more MAPKKs, 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., 2006b, 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.

Figure 4.

Axonal transport abnormalities in myelin protein-deficient mice. 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 fibers. Scale bars: B, C, 2 μm; D, E, 1 μm.

Figure 5.

Model for alteration of FAT as a mechanism leading to MPTP/MPP+-induced parkinsonism. 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 phosphorylates 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), and altered trophic factor support (Delcroix et al., 2004). These events ultimately would lead to neuronal cell death. cat, Catalytic subunit; reg, regulatory subunit.

Figure 6.

Relationships among microtubule-based molecular motors for FAT, protein kinases, and neuropathogenic polypeptides/compounds. 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 an 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; AR, androgen receptor; Htt, Huntingtin; oAβ, oligomeric β-amyloid; MPP+, 1-methyl-4-phenylpyridinium; GSK3, glycogen synthase kinase 3; JNK3, cJun-amino terminal kinase 3; CK2, casein kinase 2; PKC, protein kinase C.