CNR1 variation is associated with the age at onset in Huntington disease

Kloster, Eugen; Saft, Carsten; Epplen, Jörg T.; Arning, Larissa

doi:10.1016/j.ejmg.2013.05.007

Cited by 19 publications

(6 citation statements)

References 30 publications

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“…This may correspond to our previous finding that NMDA receptor variants that are also associated with the age of onset of HD did not show any association with TD [35]. A similar association with the age of onset in HD was found for variations in the CNR1 gene [101], but using 20 tagSNPs, which captured all variations of this gene, Tiwari et al [102] found only a weak association with TD. The only association (rs806374) was marginal after correcting for multiple testing.…”

Section: Corticostriatal and Thalamostriatal Glutamatergic Neuronssupporting

confidence: 86%

Putative Role of Pharmacogenetics to Elucidate the Mechanism of Tardive Dyskinesia in Schizophrenia

2019

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Identifying biomarkers which can be used as a diagnostic tool is a major objective of pharmacogenetic studies. Most mental and many neurological disorders have a compiled multifaceted nature, which may be the reason why this endeavor has hitherto not been very successful. This is also true for tardive dyskinesia (TD), an involuntary movement complication of long-term treatment with antipsychotic drugs. The observed associations of specific gene variants with the prevalence and severity of a disorder can also be applied to try to elucidate the pathogenesis of the condition. In this paper, this strategy is used by combining pharmacogenetic knowledge with theories on the possible role of a dysfunction of specific cellular elements of neostriatal parts of the (dorsal) extrapyramidal circuits: various glutamatergic terminals, medium spiny neurons, striatal interneurons and ascending monoaminergic fibers. A peculiar finding is that genetic variants which would be expected to increase the neostriatal dopamine concentration are not associated with the prevalence and severity of TD. Moreover, modifying the sensitivity to glutamatergic long-term potentiation (and excitotoxicity) shows a relationship with levodopa-induced dyskinesia, but not with TD. Contrasting this, TD is associated with genetic variants that modify vulnerability to oxidative stress. Reducing the oxidative stress burden of medium spiny neurons may also be the mechanism behind the protective influence of 5-HT2 receptor antagonists. It is probably worthwhile to discriminate between neostriatal matrix and striosomal compartments when studying the mechanism of TD and between orofacial and limb-truncal components in epidemiological studies.

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Section: Corticostriatal and Thalamostriatal Glutamatergic Neuronssupporting

confidence: 86%

Putative Role of Pharmacogenetics to Elucidate the Mechanism of Tardive Dyskinesia in Schizophrenia

2019

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“…In accordance with this, knockdown or knockout of CB 1 in medium spiny projection neurons of R6/2, N171-82Q, or Hdh Q150/Q150 HD mice further reduces the pool of CB 1 and exacerbates deficits in motor control, enhances striatal atrophy, and reduces survival (Blázquez et al, 2011;Mievis et al, 2011;Horne et al, 2013). Further, individuals with HD and a variant of the CB 1 gene (CNR1 rs4707436) that is associated with lower levels of CB 1 begin displaying motor-related symptoms of HD earlier than individuals with HD and normal CNR1 (Kloster et al, 2013). Together, these studies and our [ATP] was determined using the CellTiter Glo assay (Promega).…”

Section: Discussionmentioning

confidence: 99%

Biased Type 1 Cannabinoid Receptor Signaling Influences Neuronal Viability in a Cell Culture Model of Huntington Disease

et al. 2015

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Huntington disease (HD) is an inherited, autosomal dominant, neurodegenerative disorder with limited treatment options. Prior to motor symptom onset or neuronal cell loss in HD, levels of the type 1 cannabinoid receptor (CB 1 ) decrease in the basal ganglia. Decreasing CB 1 levels are strongly correlated with chorea and cognitive deficit. CB 1 agonists are functionally selective (biased) for divergent signaling pathways. In this study, six cannabinoids were tested for signaling bias in in vitro models of medium spiny projection neurons expressing wild-type (STHdh Q7/Q7 ) or mutant huntingtin protein (STHdh Q111/Q111). Signaling bias was assessed using the Black and Leff operational model. Relative activity [DlogR (t/K A )] and system bias (DDlogR) were calculated relative to the reference compound WIN55,212-2 for Ga i/o , Ga s , Ga q , Gbg, and b-arrestin1 signaling following treatment with 2-arachidonoylglycerol (2-AG), anandamide (AEA), CP55,940, D 9 -tetrahydrocannabinol (THC), cannabidiol (CBD), and THC1CBD (1:1), and compared between wild-type and HD cells. The E max of Ga i/o -dependent extracellular signal-regulated kinase (ERK) signaling was 50% lower in HD cells compared with wild-type cells. 2-AG and AEA displayed Ga i/o /Gbg bias and normalized CB 1 protein levels and improved cell viability, whereas CP55,940 and THC displayed b-arrestin1 bias and reduced CB 1 protein levels and cell viability in HD cells. CBD was not a CB 1 agonist but inhibited THC-dependent signaling (THC1CBD). Therefore, enhancing Ga i/o -biased endocannabinoid signaling may be therapeutically beneficial in HD. In contrast, cannabinoids that are b-arrestin-biased-such as THC found at high levels in modern varieties of marijuana-may be detrimental to CB 1 signaling, particularly in HD where CB 1 levels are already reduced.

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“…(Table 1). A variant of the CB 1 gene (CNR1 rs4707436) that is related with lower levels of CB 1 has been associated with age at onset in HD patients [60]. Further, mutant Htt affects CB 1 promoter activity [59] through repressor element 1 silencing transcription factor, REST, which is implicated in the pathogenesis of HD [61,62].…”

Section: The Link Between Hd and Cb 1 Receptor-mediated Protective Acmentioning

confidence: 99%

The bright side of psychoactive substances: cannabinoid-based drugs in motor diseases

Coccurello

Bisogno

2016

Expert Review of Clinical Pharmacology

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CNR1 variation is associated with the age at onset in Huntington disease

Cited by 19 publications

References 30 publications

Putative Role of Pharmacogenetics to Elucidate the Mechanism of Tardive Dyskinesia in Schizophrenia

Putative Role of Pharmacogenetics to Elucidate the Mechanism of Tardive Dyskinesia in Schizophrenia

Biased Type 1 Cannabinoid Receptor Signaling Influences Neuronal Viability in a Cell Culture Model of Huntington Disease

The bright side of psychoactive substances: cannabinoid-based drugs in motor diseases

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