Severe deficiencies in dopamine signaling in presymptomatic Huntington's disease mice

Abstract

In Huntington's disease (HD), mutation of huntingtin causes selective neurodegeneration of dopaminoceptive striatal medium spiny neurons. Transgenic HD model mice that express a portion of the diseasecausing form of human huntingtin develop a behavioral phenotype that suggests dysfunction of dopaminergic neurotransmission. Here we show that presymtomatic mice have severe deficiencies in dopamine signaling in the striatum. These include selective reductions in total levels of dopamine-and cAMP-regulated phosphoprotein, Mr 32 kDA (DARPP-32) and other dopamine-regulated phosphoprotein markers of medium spiny neurons. HD mice also show defects in dopamine-regulated ion channels and in the D1 dopamine͞DARPP-32 signaling cascade. These presymptomatic defects may contribute to HD pathology. H untington's disease (HD) is an inherited neurodegenerative disorder characterized by progressive motor, psychiatric, and cognitive disturbances. The motor disturbance begins subtly, as minor adventitious movements, and gradually progresses until the entire body is consumed in flagrant chorea and uncontrolled writhing, leading to death 10-20 years after onset (1). HD pathology is characterized by specific neurodegeneration of the caudate nucleus and putamen (2, 3). Genetic analysis has established a causative link between HD and abnormal expansion of a polyglutamine repeat in the protein huntingtin (4). The transgenic mouse line R6͞2 (HD mice) is a well-characterized animal model of HD in which a fragment of a disease-causing variant of human huntingtin is ectopically expressed. These mice exhibit HD-like behavioral changes beginning after 8 weeks of life, progressively deteriorate over the succeeding 10 weeks, and die prematurely (5, 6). Although the HD mice are essentially asymptomatic until week 8, behavioral deficits are preceded by the appearance of intranuclear inclusion bodies in the central nervous system (7,8). These inclusions are similar to those detected in HD and other diseases associated with polyglutamine expansions (7-9).Both normal and mutant huntingtin are expressed throughout the body. The dramatic and selective loss of striatal tissue seen in HD, and the resultant pronounced behavioral and pathological effects, have remained unexplained (1, 10, 11). Given that the striatum is the predominant target of midbrain dopamine neurons, we sought to determine whether dopamine signaling might be altered in presymptomatic HD mice. We found that while many parameters of neuronal function remained unchanged, there were significant deficits including severely impaired electrophysiological and biochemical responses to activation of D1-class dopamine receptors, which precede the emergence of histopathological and behavioral changes. Materials and MethodsForskolin was purchased from LC Laboratories. 8-BromocAMP and protease type XIV were purchased from Sigma. SKF81297, D1 receptor antibodies, kainic acid, dopamine, and ␥-aminobutyric acid (GABA) were purchased from Research Biochemicals. Actin antibodies were purchased from BRL....

Tauroursodeoxycholic acid, a bile acid, is neuroprotective in a transgenic animal model of Huntington's disease

“…For example, in 4-to 6-week-old presymptomatic R6͞2 mice, expression of certain striatal signaling genes, as well as proteins important for neurotransmission, is significantly reduced (54)(55)(56)(57). In addition, marked striatal and cortical neuron atrophy is detectable at 6 weeks of age (42).…”

“…In fact, there is evidence to show that HD symptomatology occurs before extensive striatal cell death (54)(55)(56)(57), and apoptosis tends to be an acute, rather than chronic, process. In fact, in the initial characterization of the R6͞2 Tg HD mouse, no significant cell death was detected.…”

Ganglioside GM1 induces phosphorylation of mutant huntingtin and restores normal motor behavior in Huntington disease mice

“…DARPP-32 is highly enriched in medium-sized spiny neurons and its down-regulation is an early marker of neuronal dysfunction in HD (40). Normalization of motor behavior in GM1-treated YAC128 mice correlated with increased striatal expression of DARPP-32 ( Fig.…”

Brain‐derived neurotrophic factor modulates dopaminergic deficits in a transgenic mouse model of Huntington's disease

“…Several reports have shown that these mice reproduce some of the dopaminergic dysfunction observed in HD patients. However, dopaminergic deficits are more apparent in the R6/2 line (Bibb et al 2000;Hickey et al 2002;Petersen et al 2002), which shows a more rapid progression of HD symptoms (Mangiarini et al 1996). These dopaminergic alterations include decreased levels of D 1 and D 2 dopamine receptors (Cha et al 1998), reduced dopamine content (Reynolds et al 1999), and age-dependent impairment in the behavioural response to dopamine stimulants (Hickey et al 2002).…”