Conclusions

In human HD, as well as symptomatic stages in HD animal models, there are a multitude of disruptions to processes that are intrinsic to neuronal function and survival. A more complete understanding of the mechanisms for neuronal and synaptic dysfunction at this stage will guide symptomatic therapy in HD and help to develop interventions to slow the course of disease. In order to delay onset of HD, it will be necessary to further investigate the earliest effects of the HD mutation on neuronal function. In this regard, increased NMDA receptor function and toxic signaling, disrupted Ca2+ homeostasis, altered dopamine modulation of neurotransmission, and perturbed axonal transport (Figure 31.1; Colorplate 13) have been identified as very early changes that precede onset of the movement disorder. These disturbances may underlie synaptic dysfunction responsible for early cognitive and personality changes, and may also provide triggers for aberrant proteolysis, proteasome dysfunction, and altered gene transcription leading to more severe neuronal dysfunction and death. Genetic testing allows those at risk for HD to be identified early, and biomarkers that will facilitate prediction of an individual's age of disease onset are being developed. With these advances, the possibilities for altering the course of this devastating neurodegenerative disease appear promising.

Figure 31.1. Summary of Alterations in Cortico-Striatal Synaptic Function Implicated in HD. Simplified figure of a cortico-striatal synapse; a cortical afferent (green) synapses with a spine of a striatal MSN (blue), astrocytes (brown) surround the synaptic cleft, and GABAergic (red) and dopaminergic (purple) terminals are also shown. Red circles indicate where positive, negative, and nonlinear alterations have been reported in HD and HD models. (1) Axonal transport along microtubules is reduced by polyQ expansion9-12, e.g., disrupted BDNF transport is associated with the detachment of a dynactin p150/HAP1/mhtt complex from microtubules and may be due to increased HAP 1/huntingtin binding produced by polyQ expansion13-15. (2) Synapsin 1 hyperphosphorylation20 may alter synaptic vesicle reserve pool regulation; this and decreased levels of the vesicular proteins complexin II23,25,26,31 and rabphilin 3A22 may perturb docking and priming of NT vesicles within the active zone (broken green line). Ca2+ influx, through N-type Ca2+ channels, triggers vesicle fusion and NT release; this influx may be increased in HD by the loss of cysteine string protein (CSP)-mediated inhibition of N-type channels32. Earlier increases and later decreases in glutamate release are observed

Figure 31.1. Summary of Alterations in Cortico-Striatal Synaptic Function Implicated in HD. Simplified figure of a cortico-striatal synapse; a cortical afferent (green) synapses with a spine of a striatal MSN (blue), astrocytes (brown) surround the synaptic cleft, and GABAergic (red) and dopaminergic (purple) terminals are also shown. Red circles indicate where positive, negative, and nonlinear alterations have been reported in HD and HD models. (1) Axonal transport along microtubules is reduced by polyQ expansion9-12, e.g., disrupted BDNF transport is associated with the detachment of a dynactin p150/HAP1/mhtt complex from microtubules and may be due to increased HAP 1/huntingtin binding produced by polyQ expansion13-15. (2) Synapsin 1 hyperphosphorylation20 may alter synaptic vesicle reserve pool regulation; this and decreased levels of the vesicular proteins complexin II23,25,26,31 and rabphilin 3A22 may perturb docking and priming of NT vesicles within the active zone (broken green line). Ca2+ influx, through N-type Ca2+ channels, triggers vesicle fusion and NT release; this influx may be increased in HD by the loss of cysteine string protein (CSP)-mediated inhibition of N-type channels32. Earlier increases and later decreases in glutamate release are observed in some HD mice18. (3) HIP1 is involved in clathrin-mediated endocytosis35, a process which may be disrupted by reduced HIP1/huntingtin binding by polyQ expansion34. In addition, htt binding of the PACSIN1 regulator of vesicle recovery increases proportionally to polyQ, and PACSIN1 is abnormally located away from the synapse in HD36. (4) Receptors, known to modulate release presynaptically, are reduced in HD48. (5) Astrocytic excitatory amino acid transporter 1 (EAAT1/GLT1) mRNA levels are reduced37 and glutamate uptake is altered in HD20,38. (6) Inhibitory GABA release is increased39,44, as is GABA receptor labeling44, possibly due to perturbations in HAP 1-regulated GABA receptor recycling81. (7) K+ channel currents and subunits are decreased in HD models47. (8) Activation of group I mGluRs results in the generation of InsP3 and mhtt facilitates the action of the mGluR inhibitory protein optineurin54 leading to reduced InsP3 signaling; however polyQ-enhanced binding between InsP3 receptor and htt results in increased Ca2+ release from intracellular stores (reviewed in ref. 53). (9) Reductions in D1 and D2 dopamine receptors are observed in HD 21,49,60,75,76-78 (reviewed in ref. 74) and increased cAMP labeling70, decreased DARPP-32 labeling, and a loss of dopaminergic modulation of other NT receptor systems is also observed21,79. D1 receptor agonism induces the redistribution of htt, HIP1 and clathrin to the membrane71 and may play a role in regulating surface expression of NMDARs. (10) Increases in NR143 and decreases in NR2A/B protein (43, but see ref. 60), in addition to altered PSD-95 interactions66,67 and differences in reported NMDAR subunit phosphorylation state49,60,67,70 together suggest that trafficking of NMDARs is altered in HD. In addition, NMDARs are internalized by clathrin-dependent endocytosis; reduced mhtt/HIP-1 binding33,34 and a breakdown in clathrin interaction may contribute to altered NMDAR surface expression. Additionally, HIP14/htt binding, which may also be important for endocytosis and protein trafficking, is also reduced by expanded polyQ (reviewed in ref. 68). (11) Altered NMDAR surface expression likely accounts for early increases in NMDAR function seen across HD models40,43,46,52,56-59. The resultant increase in Ca2+ influx, in combination with increased release from intracellular stores53, has severe implications for cortico-striatal Ca2+ signaling, phosphatase/kinase activity, and consequently synaptic plasticity and the regulation of gene transcription. Moreover, such disruptions in Ca2+ signaling and homeostasis may be the triggers for more severe neuronal dysfunction and ultimately cell death. See Colorplate 13.

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