Hypocretin and Melanin‐Concentrating Hormone in Patients with Huntington Disease

Abstract

To evaluate whether hypocretin-1 (orexin-A) and melanin-concentrating hormone (MCH) neurotransmission are affected in patients with Huntington disease (HD), we immunohistochemically stained hypocretin and MCH neurons and estimated their total numbers in the lateral hypothalamus of both HD patients and matched controls. In addition, hypocretin-1 levels were determined in prefrontal cortical tissue and post-mortem ventricular cerebrospinal fluid (CSF) using a radioimmunoassay. The total number of hypocretin-1 neurons was significantly reduced by 30% in HD brains (P = 0.015), while the total number of MCH neurons was not significantly altered (P = 0.100). Levels of hypocretin-1 were 33% lower in the prefrontal cortex of the HD patients (P = 0.025), but ventricular CSF levels were similar to the control values (P = 0.306). Neuronal intranuclear and cytoplasmic inclusions of mutant huntingtin were present in all HD hypothalami, although with a variable distribution across different hypothalamic structures. We found a specific reduction in hypocretin signaling in patients with HD as MCH cell number was not significantly affected. It remains to be shown whether the moderate decrease in hypocretin neurotransmission could contribute to clinical symptoms. As the number of MCH-expressing neurons was not affected, alterations in MCH signaling are unlikely to have clinical effects in HD patients.

Orexin system and pathogenesis of sleep-wake cycle disturbances in narcolepsy

“…При таких заболеваниях, как болезнь Паркинсона [58,59], хорея Гантингтона [60], детектировалось значительное снижение ко-личества гипоталамических орексин-содержащих нейронов (у более 50% популяции), но уровень орексина А в спинномозговой жидкости часто оставался в пределах нормы [61].…”

Huntington’s Disease – New Perspectives Based on Neuroendocrine Changes in Rodent Models

“…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 hypothalamus [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.…”

“…CART = Cocaine-and amphetamine-regulated transcript; POMC = proopiomelanocortin; MCH = melanin-concentrating hormone; ACTH = adrenocorticotropic hormone. [82,83] atrophy [90,91] Orexin loss of orexin: R6/2, YAC128 [84,86] loss of orexin [84,89] HPA axis upregulation: R6/2 [96] upregulation [96,102,104] Testosterone increased plasma levels: R6/2 [106] increased plasma 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] …”

Is HCRTR2 a Genetic Risk Factor for Alzheimer's Disease?

“…AD is a neurodegenerative disorder that affects multiple brain areas as well as types of neurons and most likely includes the primary sleep-regulating systems. As the hypocretin system is affected in various neurodegenerative diseases such as Parkinson's and Huntington's disease [8,9,10], we hypothesized that the neurodegenerative process in AD might also affect the hypocretin system, which could contribute to the sleep disturbances of AD patients. The observation of Friedman et al [11], who have shown an inverse relation between lumbar CSF hypocretin-1 concentration and the amount of daytime naps of AD patients, supports this possibility.…”