As nuclear localization of mutant polyQ protein is limited at best in SCA2 (Huynh et al. 1999) and SCA6 (Ishikawa et al. 2001), any influence of expanded polyQ on transcription or other nuclear activities in these two diseases is probably indirect. In the polyQ diseases that are characterized by soluble or aggregated, mutant protein in the cytoplasm, it is possible that polyQ-mediated changes outside the nucleus are most relevant to pathology. In particular, both disruption of axonal transport (Gunawardena et al. 2003) and potentially related defects in synaptic function (Li et al. 2000; Usdin et al. 1999) have received considerable attention recently.
Similar to the situation in the nucleus, both soluble and aggregated polyQ may contribute to cytoplasmic problems. Neuropil aggregates have been most carefully examined in HD (Li et al. 2000), but, at least in cultured cells, expression of several polyQ disease proteins can induce their formation (Piccioni et al. 2002; Gunawardena et al. 2003). These cytoplasmic structures, which can localize to axons (Li et al. 1999), dendrites, or dendritic spines (Gutekunst et al. 1999), may be an early maker of HD pathology, distinguishing them from perikaryal and nuclear aggregates (Gutekunst et al. 1999; Sapp et al. 1999). In HD repeat knockin mice, neuropil aggregates form progressively in the lateral globus pallidus (LGP) and substantia nigra pars reticulata (SNr). These htt aggregates, distinct from the larger NII that abound in the nuclei of striatal neurons, reside in the axons of medium spiny neurons that project to both of these regions. The presence of neuropil aggregates, which actually can be very large relative to the size of an axon terminal, has been associated with axonal degeneration in electron micrographs. Consistent with the possibility of axonal occlusion, synaptic vesicles are less abundant in terminals that harbor aggregates (Li et al. 2001). The neuropathology in this HD mouse line recapitulates the selective neurodegeneration that occurs early in HD, as loss of striatal projection neurons that target the LGP and SNr is evident in presymptomatic patients (Albin et al. 1990, 1992). Neuritic degeneration is also observed in striatal neurons transfected with mutant htt (Li et al. 2000, 2001), and this event precedes nuclear fragmentation that is indicative of apoptosis (Li et al. 2001).
In vitro experiments indicate that polyQ-expanded htt in axonal terminals can undermine normal synaptic function. Mutant htt causes deficiencies in both glutamate uptake by synaptic vesicles (Li et al. 2000) and glutamate release into the synaptic cleft during high-frequency stimulation. The latter phenomenon, which results in reduced long-term potentiation (Usdin et al. 1999), may contribute to cognitive impairments characteristic of HD patients. Moreover, defects in synaptic transmission should ultimately impact neuronal viability (J.Y. Li et al. 2003). Interestingly, the synaptic disturbances might be explained by the direct binding of htt fragments to synaptic vesicles, since the strength of the interaction is enhanced by polyQ expansion (Li et al. 2000). As various proteins involved in synaptic activities interact with normal htt (Li and Li 2004a), it is unclear if other polyQ diseases may also be characterized as synaptopathies.
The presence of expanded polyQ in neuronal process also dramatically affects fast axonal transport (FAT) (Morfini et al. 2005; Gunawardena and Goldstein 2005). Several ideas have been proposed to explain the mechanism by which mutant polyQ proteins block the movement of microtubule-based molecular motors in axons (Fig. 4). Physical obstruction by neuropil aggregates (Lee et al. 2004; Gunawardena et al. 2003), which increase in size with disease progression (Gutekunst et al. 1999), is an attractive possibility. In late-stage HD, neuropil aggregates in excess of 30 nm2 are not uncommon, but even the smaller aggregates that predominate in early HD could at least partially occlude a typical nonmotor axon. Alternatively, titration of motor proteins away from microtubules by aggregated (Trushina et al. 2004) or soluble, mutant polyQ could undermine axonal trafficking; however, these explanations are not supported by in vitro experiments carried out in squid axoplasm with purified polyQ proteins (Morfini et al. 2005). Both polyQ-expanded androgen receptor and mutant N-terminal htt, but not the normal versions of these proteins, antagonize FAT in this context. Inhibition occurs upon addition of either mutant protein to the isolated axoplasm at a concentration 100-fold lower than endogenous levels of trafficking motors and in the absence of any detectable aggregation (Szebenyi et al. 2003; Morfini et al. 2005).
It is now clear that normal htt, unlike the other polyQ disease proteins, has a role in axonal transport (Gunawardena et al. 2003; Gauthier et al. 2004; Trushina et al. 2004) (Table 2); thus, loss of normal htt function as a result of polyQ expansion might contribute to FAT inhibition in HD. There is at present no evidence of diminished htt function in the presence of other polyQ-expanded proteins. It is also conceivable that disruption of certain in-tracellular signaling pathways could undermine FAT, but specific pathways
Fig. 4 Disruption of microtubule-based transport by cytoplasmic, polyQ-expanded proteins. Both soluble and aggregated versions of mutant polyQ can sequester trafficking proteins. Also, aggregated polyQ may sterically hinder transport in narrow-diameter axons. As low concentrations of mutant polyQ are capable of antagonizing transport in vitro, other possibilities may also account for observed disturbances in axonal trafficking
Fig. 4 Disruption of microtubule-based transport by cytoplasmic, polyQ-expanded proteins. Both soluble and aggregated versions of mutant polyQ can sequester trafficking proteins. Also, aggregated polyQ may sterically hinder transport in narrow-diameter axons. As low concentrations of mutant polyQ are capable of antagonizing transport in vitro, other possibilities may also account for observed disturbances in axonal trafficking or kinases have yet to be directly implicated in this polyQ-mediated effect (Morfini et al. 2005).
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