Huntingtons Disease - New Perspectives Based on Neuroendocrine ...

Modeling Neurodegenerative Diseases in vivo

Diseases

Neurodegenerative Dis 2009;6:154–164 DOI: 10.1159/000225377

Received: January 11, 2009 Accepted after revision: March 11, 2009 Published online: June 12, 2009

Huntington’s Disease – New Perspectives Based on Neuroendocrine Changes in Rodent Models Åsa Petersén a Sofia Hult a Deniz Kirik b a Translational Neuroendocrine Research Unit, and b Brain Repair and Imaging in Neural Systems (BRAINS), Department of Experimental Medical Science, Lund University, Lund, Sweden

Key Words Huntington’s disease ! Neuroendocrine ! Mouse ! Rat ! Hypothalamus ! Model

knowledge derived from neuroendocrine studies in rodent models of HD in light of clinical relevance and points to future implications for this emerging field. Copyright © 2009 S. Karger AG, Basel

Abstract Huntington’s disease (HD) is a neurodegenerative disorder caused by an expanded CAG repeat in the huntingtin gene. Although it is characterized by progressive motor impairments, cognitive changes and psychiatric disturbances are major components of the disease. In addition, recent studies have shown that other non-motor symptoms such as alterations in sleep pattern, disruption of the circadian rhythm and increased energy metabolism are common and occur early. Emerging evidence suggests that the latter symptoms are likely results of disturbed functions of the hypothalamus and neuroendocrine circuits, which are known to be central in the regulation of emotion, sleep and metabolism. Whereas clinical data are essential to define key pathological features of HD, animal models that can recapitulate the neurobiological and behavioral features of the disorder are critical tools to elucidate the underlying pathogenic mechanisms. Recent studies employing different HD rodent models have been instrumental in identifying a number of neuroendocrine alterations as well as in highlighting novel potential disease pathways. This review summarizes the current state of

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Introduction

Huntington’s disease (HD) is an autosomal dominant neurodegenerative disorder caused by an expanded CAG repeat in the huntingtin gene [1]. The huntingtin protein is expressed ubiquitously throughout the central nervous system and peripheral tissues both during embryonic development and adult life [2–4]. The normal function of huntingtin is not fully known but is thought to involve regulation of transcription, intracellular trafficking, synaptic vesicle exocytosis as well as apoptosis [5, 6]. The classic triad of clinical symptoms comprises motor impairments, cognitive decline and psychiatric disturbances, and was first comprehensively described in the literature in 1872 by the clinician George Huntington, who gave the disease its name [7]. Depressed mood, anxiety, irritability and apathy are the most common psychiatric symptoms and have been reported to affect between 35 and 75% of HD cases in different patient series [8]. These symptoms usually precede motor abnormalities by many Assoc. Prof. Åsa Petersén, MD, PhD Translational Neuroendocrine Research Unit BMC D11 SE–22184 Lund (Sweden) Tel. +46 46 222 1686, Fax +46 46 222 3436, E-Mail [email protected]

years [9, 10]. Despite intense research during the last decades, the disease still has no cure. The symptomatic treatment has improved significantly, however, and it has especially benefited from the increased awareness of nonmotor symptoms (see Phillips et al. [11] for a recent review on clinical management). The neuropathological stage of HD is determined based on the extent of neuropathology in the striatum, the most affected region in HD [12]. Severe atrophy also occurs in the cerebral cortex, which is likely to be important for the cognitive decline [13, 14]. Aggregation of mutant huntingtin into neuronal intranuclear inclusions is a hallmark of the disease and occurs in several brain regions [15]. It is yet not clear, however, whether these inclusions are toxic, protective or merely an epiphenomenon. Long ago, George Huntington noticed that individuals with HD suffer from emaciation. Early studies investigating body weight changes in HD found that severe weight loss occurs despite adequate nutrition [16] and that the caloric intake was increased in HD patients compared to healthy individuals [17]. Moreover, it was noted that HD patients with a high body mass index have a slower disease progression than leaner patients [18]. It was suggested early on that weight loss could be due to altered hypothalamic function [19], as it was known that alterations occur in energy metabolism in animal models with experimental lesions of hypothalamic structures (recently reviewed in Abizaid and Horvath [20]). Pioneering quantitative postmortem studies of the hypothalamus in HD demonstrated atrophy of the lateral tuberal nucleus in the hypothalamus, including loss of up to 90% of cells in this particular area [21, 22]. However, this nucleus is without known function, and no corresponding region has been found in rodents. As dopaminergic antagonists exerted a beneficial effect on chorea, it was hypothesized that dopaminergic activity was increased in brains with HD and also in the hypothalamus. Initial observations of increased levels of growth hormone (GH), which is released upon dopaminergic stimulation from the hypothalamus, supported this theory [23–25]. Follow-up studies found increased basal levels or increased release of GH after stimulation by dopaminergic agonists in HD patients [26–30]. Since dopamine stimulation inhibits prolactin release, the notion of increased dopaminergic activity gained further support from reports of reduced prolactin levels, which would be expected if the dopaminergic tone was high in the hypothalamus [31]. However, a number of other studies could not replicate the results of reduced prolactin levels [26, 32–34] or increased GH levels [32, 34]. It is possible that

these studies were limited by unreliable clinical diagnosis as the huntingtin gene was first identified in 1993. Since these early studies, it has become clear that hypothalamus and neuroendocrine circuits are not only involved in the control of body weight but are also central in the regulation of emotion and sleep. Recent studies have shown that weight loss in HD is likely due to increased energy metabolism and is correlated with CAG repeat length [35–37]. The presence of symptoms such as alterations in sleep pattern and disruption of the circadian rhythm further support that hypothalamic dysfunction occurs in HD [38–42]. With the development of transgenic animal models for HD (an overview of all HD rodent models was recently provided by Heng et al. [43]) as well as with the increasing knowledge of hypothalamic function, new possibilities have paved the way to the study of neuroendocrine and hypothalamic disturbances in HD. In fact, a number of neuroendocrine changes have now been identified in rodent models of HD. These have been important in inspiring new clinical studies in this area and have also opened new insights into the pathophysiology of HD. This review summarizes the current state of knowledge derived from neuroendocrine studies in rodent models of HD in light of clinical studies in this area, and points to future implications for this emerging field.

Huntington’s Disease – Neuroendocrine Changes in Rodent Models

Neurodegenerative Dis 2009;6:154–164

Hypothalamus and Neuroendocrine Circuits

The neuroendocrine system comprises a network of specialized neurons and endocrine cells that regulate energy metabolism, reproduction, blood pressure, mood, stress, thermoregulation, sleep, and body fluid homeostasis. These cells are localized in areas such as the hypothalamus, the pituitary, the adrenal gland, the thyroid gland, the gonads, and white adipose tissue. The hypothalamus is the major regulatory area in the neuroendocrine system. It consists of several small interconnected nuclei that together play important roles in regulating metabolism, sleep as well as emotions [44–47]. The hypothalamic nuclei receive input from the periphery and send outgoing signals to other areas of the brain as well as back to the periphery. The endocrine axes originate from neurons in the hypothalamus which express factors which in turn stimulate the release of other factors in the pituitary and are released into the blood, and then act on peripheral organs such as the adrenal gland, the thyroid gland and the gonads. The hormones released from the peripheral glands exert a negative feedback on the hypothalamic neurons to regulate the endocrine circuitry. 155

Other peripheral signals that act on the hypothalamus include ghrelin (an appetite-promoting factor derived from the stomach), leptin (a satiety factor released from adipocytes) and insulin (secreted from the pancreas) [20]. These factors enter the brain through the median eminence, which lacks a blood brain barrier and thereby regulate the activity of the arcuate nucleus, which is the most ventral part of the hypothalamus. Leptin inhibits neurons that co-express neuropeptide Y/agouti-related protein and activate neurons that co-express proopiomelanocortin (POMC)/cocaine- and amphetamine-regulated transcript (CART) in the arcuate nucleus, whereas ghrelin has the opposite effect [20]. These neurons project to orexin and melanin-concentrating hormone expressing neurons in the lateral hypothalamus where the signals are further processed and then sent to other areas of the brain as well as the periphery to regulate feeding and emotion. Thus, these peripheral hormones not only affect energy metabolism but also emotional regulation by exerting antidepressant functions [48, 49]. In fact, many other neuropeptides released from the hypothalamus are involved not only in regulation of metabolism but also emotion and sleep [45, 46]. Hence, the neuroendocrine circuitry is complex and interregulated. Besides important input from endocrine signals, the hypothalamus is also regulated by different neurotransmitter systems. Glutamate is the primary excitatory neurotransmitter in the hypothalamus, and all hypothalamic neuroendocrine populations receive glutamatergic input, and express both ionotropic and metabotropic glutamate receptors [50]. Recent studies indicate that these neurons c-release glutamate together with their hormone [51]. Furthermore, endocrine changes have been found to regulate the expression of vesicular glutamate transporters in hypothalamic neurons, and thereby regulate glutamate release from these cells [51]. Hypothalamic neurons also express D1 and D2 receptors, and dopaminergic input is known to modulate many hypothalamic functions, including metabolic control, and release of GH and prolactin [52, 53]. Interestingly, altered glutamatergic and dopaminergic signaling has been proposed as a contributing factor to selective striatal cell death observed in HD [5, 54–56]. Considering that not only the striatum but also the hypothalamus receives glutamatergic and dopaminergic input, this hypothesis could potentially be valid also for the vulnerability of specific hypothalamic neurons in HD. Hence, alterations in dopaminergic and/or glutamatergic signaling in the hypothalamus could lead to dysfunction and/or death of specific neuroendocrine populations, which 156


would then affect the neuroendocrine circuitry. In fact, the lateral tuberal nucleus that is severely affected in HD expresses a high density of glutamate receptors [57] and downregulation of hypothalamic D2 receptors has recently been found in a positron emission tomography study of presymptomatic HD patients [58]. Taken together, when a change is observed in one component in the neuroendocrine system, it may be secondary to alterations in other parts of the system. Hypothalamic Changes in HD

Different rodent models for HD have been used to study hypothalamic and neuroendocrine changes in HD (table 1; recently reviewed in Heng et al. [43]). The most extensively studied transgenic HD model is the R6/2 mouse [59]. The R6/2 mouse constitutes the most rapidly progressing HD mouse model as it expresses the N-terminal fragment of human huntingtin encoded by exon 1 carrying around 150 CAG repeats [59]. The mice have a short life span and exhibit a number of important clinical features such as cognitive and motor disturbances, as well as neuronal intranuclear inclusions and transcriptional dysregulation [59–65]. Also, a number of hypothalamic changes have been found in this model. The hypothalamic area is atrophied as determined by postmortem analysis as well as using voxel-based morphometry of magnetic resonance images [82, 83]. However, stereological assessment of cresyl-violet-stained cells have not revealed major cell loss in this region [82]. Several distinct neuronal populations in the hypothalamus are small, however. Therefore, changes in their numbers may not be easily detected when total cell counts in the whole region are assessed. Indeed, loss of NeuN-positive neurons has been found in the lateral hypothalamic area of R6/2 mice [84]. Similarly, degenerative changes at the electron microscopic level have been detected in the hypothalamus of another transgenic mouse model of HD expressing the first 171 amino acids of the N-terminal huntingtin protein with 82 CAG repeats (the N171-82Q mouse) [60, 68, 69]. Furthermore, we have demonstrated progressive reduction in the number of orexin-expressing neurons in R6/2 mice [84]. Orexin is a neuropeptide selectively expressed in the hypothalamus, and is involved in the regulation of the sleep-wake cycle, energy metabolism as well as emotion [85]. The YAC128 mouse model expresses the full length the human huntingtin gene with 128 CAG repeats and recapitulates a number of clinical features such as motor disturbances, cognitive impairment, depressive-like behavPetersén /Hult /Kirik

Table 1. Overview on rodent models for HD used in studies of the neuroendocrine system Model

CAG expansion

Characteristics

Survival Selected ref.

R6/2 mouse

150 CAG repeats in exon 1 of the human huntingtin gene

reduced motor function, cognitive deficits, reduced anxiety-like behavior, progressive weight loss, NII, widespread central and peripheral pathology, transcriptional dysregulation

12–15 weeks

R6/1 mouse

120 CAG repeats in exon 1 of the human huntingtin gene

reduced motor function, cognitive deficits, depressive-like behavior, NII, transcriptional dysregulation

normal [59, 66, 67] life span

N171-82Q 82 CAG repeats in first 171 amino mouse acids of human huntingtin gene

reduced motor function, progressive weight loss, NII; neuropathology in the cortex, striatum and hypothalamus, altered thermogenesis

20–24 weeks

YAC128 mouse

120 CAG repeats in the full-length huntingtin gene

hyperactivity followed by hypoactivity, cognitive deficits, depressivelike behavior, increased body weight, NII, striatal neuropathology

normal [71–75] life span

CAG140 mouse

knock-in of chimeric mouse/human hyperactivity followed by hypoactivity, altered anxiety-like behavior, exon 1 containing 140 CAG repeats striatal neuropathology, NII in the mouse huntingtin gene

normal [76, 77] life span

tgHD rat

51 CAG repeats in the first 22% of the rat huntingtin gene

98 weeks

hyperactivity, cognitive deficits, reduced anxiety-like behavior, weight loss, NII, striatal neuropathology

[59–65]

[68–70]

[78–81]

NII = Neuronal intranuclear inclusions.

ior as well as striatal neuronal loss [71–74]. Loss of orexin, although to a smaller extent, has also been found in the YAC128 mouse, which is likely to represent an earlier stage than the R6/2 mice [75]. Other specific neuronal populations expressing CART, proopiomelanocortin, vasopressin and melanin-concentrating hormone have been found to decline with time in R6/2 mice [82, 86]. Whether these changes are due to loss of neurons or reduced expression of the specific neuropeptides remains to be established. Decreased expression of mRNAs for CART and vasopressin as well as oxytocin, neuropeptide Y, thyroidstimulating-hormone-releasing hormone and presomatostatin have been demonstrated in a transgenic mouse model expressing a mutant truncated N-terminal fragment of huntingtin with 190 CAG repeats as well as in R6/2 mice [87]. Reduced expression of the clock genes mPer2, mBma11 as well as the vasoactive intestinal polypeptide in the suprachiasmatic nucleus, an important regulator of the diurnal rhythm, have also been found in R6/2 mice [38, 88]. Taken together, these results suggest broad transcriptional changes in the hypothalamus of at least two rodent models of HD. Neuropathological analyses of the human HD hypothalamus are sparse. The finding of reduced numbers of orexin neurons in the rodent models (10–70%) have now been established in human HD where there is a decrease of around 30% of orexin-positive neurons in the hypo-

thalamus [84, 89]. Hypothalamic atrophy, similar to that detected in R6/2 mice, has been reported in two clinical studies using voxel-based morphometry of magnetic resonance images from early HD patients [90, 91], but detailed neuropathological studies examining the survival of distinct neuronal subtypes in the whole hypothalamic region in human HD have yet to be performed.



Alterations in the Hypothalamic-Pituitary-Adrenal Axis

The hypothalamic-pituitary-adrenal (HPA) axis begins with corticotropin-releasing factor (CRF) and vasopressin produced by the parvocellular neurons in the paraventricular nucleus of the hypothalamus. These neurons integrate information relevant to stress and receive input from limbic regions implicated in emotion regulation such as the prefrontal cortex, hippocampus and the amygdala (reviewed in Herman et al. [92]). CRF and vasopressin activate the secretion of adrenocorticotropic hormone from the pituitary, which in turn stimulates the release of glucocorticoids (corticosterone in rodents; cortisol in humans) produced in the adrenal gland. Glucocorticoids then act on glucocorticoid receptors and mineralocorticoid receptors present in the hypothalamus, the pituitary as well as the hippocampus. Glucocorticoids 157

exert a negative feedback on the HPA axis both in the hypothalamus and the pituitary. The activated HPA axis exerts effects on both energy metabolism and immunity as well as on the regulation of cognitive and emotional functions [93, 94]. Increased activity of the HPA axis has been one of the most consistent findings in depression, and is thought to be a result of decreased responsiveness to glucocorticoids due to decreased function of glucocorticoid receptors. This phenomenon is known as glucocorticoid resistance and contributes to excessive inflammation as well as hyperactivity of CRF [94, 95]. We have previously reported that the HPA axis is upregulated in R6/2 mice [96]. These mice exhibit a progressive increase in corticosterone levels in serum and urine, and display typical consequences of an up-regulated HPA axis such as reduced bone mineral density, insulin resistance, muscle atrophy and reduced neurogenesis [96– 100]. The R6/1 mouse, which expresses the same N-terminal fragment of the human HD gene as the R6/2 mouse but with only 120 CAG repeats, has normal corticosterone levels [59, 66]. The R6/1 displays a slower progressive phenotype than R6/2 mice with behavioral symptoms including depressive-like behavior as well as transcriptional dysregulation [66, 67]. Whether increased activity of the HPA axis is present in other transgenic models of HD is not yet known. The underlying mechanism responsible for the upregulated HPA axis in R6/2 mice has not been established. The recently described early immune activation with increased levels of IL-6 in R6/2 and YAC128 mice as well as in premanifest HD patients [101] could play a role as increased levels of cytokines can activate the HPA axis [93, 94]. Interestingly, inflammatory cytokines and their signaling pathways, including nuclear factor!B, have been found to inhibit glucocorticoid receptor function and thereby to induce glucocorticoid resistance, and increased levels of cytokines such as IL-6 have repeatedly been found in depression [93, 95]. Hence, upregulation of both the HPA axis and the immune system in HD may have relevance for the psychiatric disturbances as well as for wider hypothalamic disturbances as microglia activation was recently found to be present in the hypothalamus of premanifest HD subjects [58, 93, 94]. Only a few studies have so far examined the HPA axis in HD patients. Increased CRF levels have been found in the cerebrospinal fluid from patients with early HD [102]. Increased cortisol and vasopressin levels have been found in plasma and urine in clinical HD [86, 96,103, 104]. Ongoing studies in different laboratories are now examining these changes in further detail.

158


Alterations in the Hypothalamic-Pituitary-Gonad Axis

The hypothalamic-pituitary-gonad axis consists of gonadotropin-releasing hormone (GnRH) expressed in the hypothalamus, luteinizing hormone and folliclestimulating hormone released from the pituitary, and testosterone or estrogen produced in the gonads. Recent studies indicate that this axis is disturbed in obesity [105]. While there is a progressive reduction in the number of GnRH-expressing neurons in the R6/2 mouse, no changes have been found in the YAC128 mouse model [106, 107]. It is not known whether the GnRH-producing population in the human HD hypothalamus is affected. Both R6/2 and YAC128 mice display the testicular atrophy which has been found in HD patients, but only the R6/2 mouse recapitulates the clinically reduced testosterone levels in male HD patients [106–108]. A recent study investigated peripheral sex hormones in a rat model for HD expressing 51 CAG repeats in the first 22% of the huntingtin gene (tgHD rat) [78, 79]. This model recapitulates several important clinical aspects of HD such as hyperactivity, cognitive deficits, weight loss as well as striatal neuropathology [78–81]. Reduced testosterone levels and increased levels of dehydroepiandrosterone sulfate (DHEA; the major androgen secreted by the adrenals) were found in female tgHD rats [79]. However, female HD patients do not show alterations in testosterone or DHEA [109] and studies in male HD patients revealed reduced DHEA levels [104]. Interestingly, male tgHD rats displayed biphasic alterations in 17"-estradiol with increased levels in 4-month-old rats and decreased levels in 14-month-old rats compared to wild-type littermates [79]. This hormone has not yet been examined in clinical HD. Alterations in Peripheral Hunger and Satiety Signals Including Peripheral Neuroendocrine Pathology in HD

White adipose tissue has emerged as an important neuroendocrine regulator of energy metabolism through its secretion of factors such as leptin and adiponectin that act on the hypothalamus [110–112]. Abnormalities in adipocytes including a disturbed lipolysis were first found in R6/2 mice [76]. A recent study investigated adipocyte function in both R6/2 mice and a knock-in mouse model for HD, the CAG140 mouse, and found impaired expression of fat storage genes [77]. The CAG140 mouse model Petersén /Hult /Kirik

expresses a chimeric mouse/human exon 1 containing 140 CAG repeats inserted into the mouse huntingtin gene and displays a slow progression of motor and cognitive disturbances as well as striatal neuropathology [113, 114]. Adipocyte function has not yet been studied in clinical HD. Decreased levels of leptin have been found in N17182Q mice, R6/2 mice, CAG140 mice [77, 115] and in clinical HD [116]. Interestingly, increased levels of leptin were found in younger stages of the CAG140 mice, which represent earlier disease stages than the other mouse models [77]. This finding indicates a biphasic pattern of leptin changes. As changes in adipokines were found prior to weight loss and behavioral symptoms in the R6/2 and CAG140 mice, these may be important for disease progression, and measurements of adipokines in presymptomatic HD gene carriers would therefore be very interesting. Reports of reductions in ghrelin both in plasma and in the stomach mucosa in R6/2 mice and N171-82Q mice [82, 115] are however opposite to the increased plasma levels found in HD patients [116]. The findings of reduced levels of leptin and increased levels of ghrelin in clinical HD support a state of negative energy balance, as leptin levels are usually reduced to preserve energy whereas increased ghrelin levels serve to increase the energy stores. A negative energy balance caused by an increased metabolic rate has recently been demonstrated in N17182Q mice, R6/2 mice and HD patients [35, 37, 70, 82, 117], although the link to hypothalamic dysfunction remains to be fully established. Importantly, peripheral changes in mitochondria due to transcriptional interference of PPAR# coactivator 1$ (PGC1$), a key regulator of metabolism, may also lead to weight loss in HD [70]. Interestingly, it has been shown that cold challenge of the N171-82Q mouse leads to hypothalamic-driven sympathetic upregulation of PGC1$ in brown adipose tissue, which suggested normal hypothalamic regulation of temperature [70]. In this study, the altered temperature control and weight loss were found to rise from interference on the level of PGC1$ transcription of the uncoupling protein 1, the main effector of adaptive thermogenesis in mitochondria. This result indicated an interesting link between altered PGC1$ function, transcriptional dysregulation and mitochondrial dysfunction in HD. Despite initial and exciting reports on severe pancreatic pathology in R6/2 mice including reduced beta cell mass, reduced exocytosis and altered pancreatic gene expression [118–120], histological and gene expression analyses of human HD pancreas have not revealed any pathological changes [121]. R6/1 and R6/2 mice have repeatedly been found to have increased glucose levels and Huntington’s Disease – Neuroendocrine Changes in Rodent Models

impaired glucose tolerance indicative of a diabetic phenotype [61, 96, 115, 118–120, 122]. Several of these studies have also reported that both R6/2 and N171-82Q mice develop insulin resistance [96, 115]. Interestingly, traditional treatments targeting the diabetic-like phenotype with insulin and metformin have had no effects on these mice [123, 124]. Importantly, a recent study using a glucagon-like peptide 1 receptor agonist, exendin 1, reported beneficial effects on changes in insulin, glucose and leptin as well as on motor performance and life span in N17182Q mice [115]. In this article, it was suggested that insulin resistance develops from defective insulin/phosphoinositide 3-kinase signaling in the hypothalamus, which is accompanied with the observed reduced leptin levels [115]. Further studies are, however, needed to establish this causative link. Insulin resistance may be a clinical feature of HD as it was recently found that HD patients with a normoglycemic state exhibit impaired insulin secretion and develop insulin resistance [125]. Altered glucose metabolism per se is less likely to be a clinical HD feature. Although earlier studies have indicated that 10– 25% of HD patients exhibit altered glucose metabolism [126], more recent studies have reported normal blood glucose levels [115, 125]. Summary and Perspectives

Animal models of neurodegenerative disorders are useful tools to discover novel pathological features as well as to elucidate underlying pathogenic mechanisms. Recent studies employing different HD rodent models have been instrumental in identifying a number of neuroendocrine changes as well as in highlighting novel potential disease pathways (table 2). The R6/2 mouse with its severe pathology has played a particularly important role in the emergence of novel candidate mechanisms for neuroendocrine changes in HD. On one hand, several neuroendocrine changes that are present in clinical HD were first detected, while the importance of others was re-discovered using this model. These changes include hypothalamic pathology with loss of orexin neurons, upregulation of the HPA axis, reduced leptin levels and insulin resistance (table 3). On the other hand, as for every other model system, the R6/2 model has its limitations. First, the expression of an artificially short fragment of the huntingtin gene with a very long CAG repeat causes a widespread pathology and a representation of late to end-stage HD in this mouse. Thus a number of changes that have been detectNeurodegenerative Dis 2009;6:154–164

159

Table 2. Overview on neuroendocrine changes in rodent models

Table 3. Neuroendocrine changes in rodent HD models that have been confirmed in clinical HD

Neuropeptide or hormone

Areas

for HD

Model

Hypothalamic expression Orexin R6/2 YAC128 CART, POMC, MCH R6/2 Vasopressin R6/2 CRF R6/2 Serum levels ACTH Corticosterone Leptin Ghrelin Adiponectin Testosterone DHEA Estradiol Insulin Glucose

R6/2 R6/2 R6/2 NI71-82Q CAG140 R6/2 N171-82Q R6/2 N171-82Q CAG140 R6/2 tgHD rat tgHD rat tgHD rat R6/2 NI71-82Q R6/2 R6/1 NI71-82Q

Change

Reference

Hypothalamus atrophy: R6/2 [82, 83] 70% loss 10% loss

[84] [86]

reduced reduced reduced

[82] [86] [96]

increased increased reduced reduced biphasic reduced reduced reduced reduced reduced reduced increased increased biphasic biphasic reduced increased increased increased

[96] [96] [77] [115] [115] [82] [115] [11] [115] [77] [106] [79] [78] [79] [96, 120] [115] [61, 118–120] [122] [115]

CART = Cocaine- and amphetamine-regulated transcript; POMC = proopiomelanocortin; MCH = melanin-concentrating hormone; ACTH = adrenocorticotropic hormone.

ed in this model might simply not be present in the majority of the clinical HD populations. Secondly, the large range of both central and peripheral changes in the R6/2 model may render mechanistic studies difficult. Models representing an earlier stage of HD or new model systems where the expression of the transgene can be controlled spatially and temporally may therefore serve as more useful tools to dissect the underlying mechanism of the neuroendocrine changes. To date, however, relatively few studies are published examining neuroendocrine aspects in other rodent models of HD. Preclinical studies utilizing a variety of models with complementary but distinct disease-related relevance will enable more rapid testing of hypotheses as well as establishment of causative 160

Animal model


Clinical HD atrophy [90, 91]

Orexin

loss of orexin: R6/2, YAC128 loss of orexin [84, 86] [84, 89]

HPA axis

upregulation: R6/2 [96]

Testosterone

increased plasma levels: R6/2 increased plasma [106] levels [108]

Insulin

insulin resistance: R6/2, N171-82Q [96, 115]

insulin resistance [125]

Leptin

decreased plasma levels: R6/2, N171-82Q, CAG140 [77, 115]

decreased plasma levels [116]

upregulation [96, 102, 104]

relationships between biological changes and behavior. While performing such studies in model systems, it will be essential to retain a parallel effort to validate the findings in HD patients in order to ascertain the clinical relevance of the discoveries. It is also likely that important lessons can be learnt from studies in the fields of depression and obesity where similar, if not identical, changes occur in the neuroendocrine and immune systems [46– 48, 84, 85]. The identification of neuroendocrine and hypothalamic changes in HD, the definition of their precise relationship to alterations in immune and neurotransmitter systems and how they cause behavioral abnormalities in patients will lead us to better understand underlying mechanisms of nonmotor symptoms. In our view, such precise mechanistic information will be critical in the development of novel therapeutic strategies, especially those aiming at intervention at early stages and modification of the natural progression of HD. Acknowledgements The authors were supported by the Swedish Medical Research Council (grant M2006-6238 to Å.P. and 2007-61x-14552-05-3 to D.K.) and CHDI (Å.P. and D.K.).

Petersén /Hult /Kirik

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