ABSTRACT
Huntington's disease is caused by an abnormal CAG expansion within the gene encoding Huntingtin which induces a major cortico-striatal degeneration as well as motor and cognitive impairments. Since the discovery of the present mutation, a number of experimental data have been collected to uncover the physiopathological consequences of mutated Huntingtin expression. Here, we review the molecular and cellular mechanisms underlying and show how this better knowledge can be translate to clinical trials in patients.
Subject(s)
Huntington Disease/pathology , Neurons/pathology , Clinical Trials as Topic , Cognition Disorders/etiology , Humans , Huntingtin Protein , Huntington Disease/genetics , Huntington Disease/therapy , Movement Disorders/etiology , Movement Disorders/pathology , Nerve Tissue Proteins/genetics , Nuclear Proteins/geneticsABSTRACT
Huntington's disease is caused by an abnormal CAG expansion within the gene encoding Huntingtin which induces a major cortico-striatal degeneration as well as motor and cognitive impairments. Since the discovery of the present mutation, a number of experimental data have been collected to uncover the physiopathological consequences of mutated Huntingtin expression. Here, we review the therapeutic challenges of Huntington's disease.
Subject(s)
Huntington Disease/pathology , Huntington Disease/therapy , Cell Death , Genetic Therapy , Humans , Huntington Disease/genetics , Nerve Degeneration/genetics , Nerve Degeneration/pathology , Neurons/pathology , Transcription, GeneticABSTRACT
In the adult mammalian brain, neural stem cells persist in the subventricular zone (SVZ) where dopamine D3 receptors are expressed. Here, we demonstrate that addition of 1 microm apomorphine increases cell numbers in post-natal SVZ cell cultures. This effect was prevented by a co-treatment with haloperidol, sulpiride or U-99194A, a D3-preferring antagonist, and mimicked by the dopamine D3 receptor selective agonist 7-hydroxy-dipropylaminotetralin (7-OH-DPAT). EC50 values were 4.04 +/- 1.54 nm for apomorphine and 0.63 +/- 0.13 nm for 7-OH-DPAT, which fits the pharmacological profile of the D3 receptor. D3 receptors were detected in SVZ cells by RT-PCR and immunocytochemistry. D3 receptors were expressed in numerous beta-III tubulin immunopositive cells. The fraction of apoptotic nuclei remained unchanged following apomorphine treatment, thus ruling out any possible effect on cell survival. In contrast, proliferation was increased as both the proportion of nuclei incorporating bromo-deoxyuridine and the expression of the cell division marker cyclin D1 were enhanced. These findings provide support for a regulatory role of dopamine over cellular dynamics in post-natal SVZ.