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The Study of Pathophysiological Function of the Striatal GABAergic Neurons in Huntington’s Disease

The Study of Pathophysiological Function of the Striatal GABAergic Neurons in Huntington’s Disease
Alternative Author(s)
Kim, Woori
Issue Date
mutant huntingtin-exon 1 with 144 CAG repeat HD transgenic mice (R6/2) and mutant 72 CAG repeat huntingtin full-length HD transgenic mice (YAC72). We found increases of both BDNF expression, and MCII/III activities in YAC72 transgenic mice, and no change of BDNF expression in R6/2 mice. Our data show that canges in HD patients for UPS function, BDNF expression and MCII/III activity are only partially modeled in R6/2 and YAC72 mice, with the latter at 16 months of age being most congruent with the human disease. In the second series of experiments we determined how to enhance UPS function and influence catalytic protein degradation and cell survival in HD. Proteasome activators involved in either the ubiquitinated or the non-ubiquitinated proteolysis were overexpressed in HD patients’ skin fibroblasts or mutant huntingtin-expressing striatal neurons. Following compromise of the UPS, overexpression of the proteasome activator subunit PA28γ, but not subunit S5a, recovered proteasome function in the HD cells. PA28γ also improved cell viability in mutant huntingtin-expressing striatal neurons exposed to pathological stressors, such as the excitotoxin quinolinic acid and the reversible proteasome inhibitor MG132. These results demonstrate the specific functional enhancements of the UPS that can provide neuroprotection in HD cells. In the third series of experiments we determined the effect of PA28γ overexpression in the HD mouse model containing the full-length human huntingtin gene with 128 CAG repeats (YAC128). We stereotaxically injected lenti-PA28γ virus into the striatum of wild-type littermates and mutant YAC128 HD transgenic mice, and validated biochemical and behavioral changes. In the proteolytic activities, PGPH activity significantly increased in the striatum of lenti-PA28γ injected mutant YAC128 mice. Importantly, both wild-type and mutant YAC128 mice showed significantly improved latency on the rotarod. Rearing and wall-rearing episodes are both reduced in mutant YAC128 mice after PA28γ overexpression. These data demonstrate that the overexpression of specific proteasome activator, PA28γ can recover behavioral abnormalities in HD model mice. In the final series of experiments we determined the effects of the stimulation of GABAergic neuron on the protein degradation mechanism in vitro and in vivo models of HD, using specific GABAB receptor agonist, baclofen. Interestingly, chymotrypsin-like proteasome activities and cell viability significantly increased in the mutant huntingtin expressing striatal cells. The expression levels of activated extracellular signal-regulated protein kinase 1/2 (ERK1/2) increased both in the wild-type and mutant huntingtin expressing striatal cells after baclofen treatment. Next, we systemically administered baclofen to YAC128 HD transgenic mice. Notably, mutant YAC128 mice exhibited increased chymotrypsin-like proteasome activity and reduced numbers of ubiquitin-positive NIIs in striatum. Finally, mutant YAC128 mice indicated markedly improved behavior abnormalities in the rotarod test. These data suggest that the stimulation of GABAergic neurons can enhance UPS function and cell survival in vitro and in vivo models of HD. Taken together, these results suggest that functional enhancement of the UPS by overexpression of proteasome activator, PA28γ and activation of GABAergic neurons via GABAB receptor stimulation, can provide neuroprotection and improvement of motor coordination in HD models. In conclusion, our findings suggest proteasome activator and GABAB receptor agonist can be promising therapeutic approaches for HD.; Huntington’s disease (HD) is an autosomal dominant inherited disease characterized clinically by a progressive movement and psychiatric disorder. HD is caused by mutations in exon 1 of the huntingtin gene (> 36 CAG). In patients with HD, the GABAergic medium-sized spiny neurons (MSNs) in the striatum show selective dysfunction and degeneration associated with the involuntary movement of HD. The neuropathological hallmark of HD is the ubiquitin-positive neuronal intranuclear inclusions (NIIs) of mutant huntingtin. One potential cause for such abnormal protein aggregation is dysfunction of the ubiquitin-proteasome system (UPS), which is essential for the degradation of abnormal, mutated or misfolded proteins. Previous evidences demonstrated the inhibited proteasome activities in several brain regions of HD patients including striatum. Herein we attempt to improve proteasome activity and neuronal survival in HD model systems for therapeutic approach for HD. In the first series of experiments we determined biochemical changes including proteasome activity, expression of brain-derived neurotrophic factor (BDNF) and mitochondrial complex II/III (MCII/III) activities related to HD pathology, in two types of widely used HD transgenic model mice
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