Regulation of motor proteins, axonal transport deficits and adult-onset neurodegenerative diseases

Abstract

Neurons affected in a wide variety of unrelated adult-onset neurodegenerative diseases (AONDs) typically exhibit a "dying back" pattern of degeneration, which is characterized by early deficits in synaptic function and neuritic pathology long before neuronal cell death. Consistent with this observation, multiple unrelated AONDs including Alzheimer's disease, Parkinson's disease, Huntington's disease, and several motor neuron diseases feature early alterations in kinase-based signaling pathways associated with deficits in axonal transport (AT), a complex cellular process involving multiple intracellular trafficking events powered by microtubule-based motor proteins. These pathogenic events have important therapeutic implications, suggesting that a focus on preservation of neuronal connections may be more effective to treat AONDs than addressing neuronal cell death. While the molecular mechanisms underlying AT abnormalities in AONDs are still being analyzed, evidence has accumulated linking those to a well-established pathological hallmark of multiple AONDs: altered patterns of neuronal protein phosphorylation. Here, we present a short overview on the biochemical heterogeneity of major motor proteins for AT, their regulation by protein kinases, and evidence revealing cell type-specific AT specializations. When considered together, these findings may help explain how independent pathogenic pathways can affect AT differentially in the context of each AOND.

Keywords: Alzheimer's disease; Amyotrophic lateral sclerosis; Axonal transport; Dynen; Huntington's disease; Kinases; Kinesin; Neurodegeneration; Parkinson's disease; Signaling.

Figure 1

A) Schematic depicting the subunit organization of conventional kinesin holoenzymes. The head domain of kinesin heavy chains (kinesin-1, KIF5s) contains protein motifs for microtubule binding and ATP hydrolysis. Joined by a short neck linker region, the long stalk features coiled-coil and hinge domains mediating homodimerization of kinesin-1s. In addition, kinesin-1s contain a globular tail domain unique to each kinesin-1 subunit variant. On the other hand, KLC subunits associate with the tail domain of conventional kinesin through heteromeric coiled coil domains. Both the carboxy terminus of KLCs and the tail domain of kinesin-1s play a role on the targeting of conventional kinesin variants to MBOs of unique protein composition. Cytoplasmic dynein has a more complex composition with multiple subunits. Unlike kinesin, there is only one gene for the cytoplasmic dynein heavy chain, but other subunits are more diverse. For example, there are two dynein intermediate chain genes and they may exhibit alternative splicing as well as post-translation modification. Thus, molecular motor featuring unique subunit combinations may associate with specific cargoes and may be subject to different signaling pathways for regulation. B) Kinesin-1s and KLCs are organized as homodimers within the conventional kinesin holoenzyme (Deboer et al., 2008), potentially giving rise to six different conventional kinesin variants. In addition, KLC1 undergoes alternative splicing, potentially increasing the number and complexity of such variants. Similarly, cytoplasmic dynein may have either DIC1 or DIC2 as well as variability in other subunits and adapter proteins such as dynactin. The diversity in motors may allow interaction with different cargos (i.e. APP-containing vesicles preferentially interact with kinesin-1C (Szodorai et al., 2009) and signaling endosomes preferentially interact with cytoplasmic dynein containing DIC1 (Ha et al., 2008)) or may allow differential regulation (i.e. GSK3β preferentially modifies KLC2 (Morfini et al., 2002)).

Figure 2

Three genes encoding kinesin-1 subunits are expressed in mammalian nervous system: kinesin-1A (KIF5A), kinesin-1B (KIF5B), and kinesin-1A (KIF5C). Antibodies that selectively recognize each one of these subunits (Deboer et al., 2008) reveal a unique distribution pattern for each subunit in different regions of the central nervous system, suggesting that different neurons display a unique complement of conventional kinesin heavy chain subunit variants: Br whole brain; ON optic nerve; SC spinal cord; SN sciatic nerve; OB olfactory bulb, CCX cerebral cortex; HIP hippocampus; and CB cerebellum. Note that kinesin-1A is widely expressed in nervous tissue, but that there are quantitative differences in different regions. Kinesin-1B and kinesin-1C show more variability among brain regions. This and other observations imply cell type-specific specializations of axonal transport rarely recognized in the literature, which may contribute to the selective vulnerability of specific neuronal populations in different AONDs.

Figure 3

Axonal transport is disrupted by the presence of pathogenic forms of normal neuronal proteins, which lead to activation of specific kinase signaling pathways. For example, tau filaments activate a phosphatase PP1/GSK3P pathway (Kanaan et al., 2011), which preferentially phosphorylates conventional kinesin motors containing KLC2 (Morfini et al., 2002). This phosphorylation in turn leads to release of kinesin from the associated cargo vesicle. Similarly, pathogenic forms of huntingtin activate a MAP kinase pathway leading to JNK3, which preferentially phosphorylates motors containing kinesin-1B and -1C subunits and inhibits their interaction with microtubules (Morfini et al., 2009b). JNK3 also inhibits retrograde AT, but the specific cytoplasmic dynein subunit that is modified has not been identified.