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. 2011 Aug 23:5:55.
doi: 10.3389/fnana.2011.00055. eCollection 2011.

Huntington's Disease and Striatal Signaling

Emmanuel Roze  1 , Emma Cahill, Elodie Martin, Cecilia Bonnet, Peter Vanhoutte, Sandrine Betuing, Jocelyne Caboche
Affiliations

Huntington's Disease and Striatal Signaling

Emmanuel Roze et al. Front Neuroanat. .

Abstract

Huntington's Disease (HD) is the most frequent neurodegenerative disease caused by an expansion of polyglutamines (CAG). The main clinical manifestations of HD are chorea, cognitive impairment, and psychiatric disorders. The transmission of HD is autosomal dominant with a complete penetrance. HD has a single genetic cause, a well-defined neuropathology, and informative pre-manifest genetic testing of the disease is available. Striatal atrophy begins as early as 15 years before disease onset and continues throughout the period of manifest illness. Therefore, patients could theoretically benefit from therapy at early stages of the disease. One important characteristic of HD is the striatal vulnerability to neurodegeneration, despite similar expression of the protein in other brain areas. Aggregation of the mutated Huntingtin (HTT), impaired axonal transport, excitotoxicity, transcriptional dysregulation as well as mitochondrial dysfunction, and energy deficits, are all part of the cellular events that underlie neuronal dysfunction and striatal death. Among these non-exclusive mechanisms, an alteration of striatal signaling is thought to orchestrate the downstream events involved in the cascade of striatal dysfunction.

Keywords: Huntingtin; excitotoxicity; mitochondrial dysfunctions; polyglutamine; transcriptional deregulation.

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Figures

Figure 1
Figure 1
Altered striatal signaling pathways in HD. Afferent corticostriatal and nigro-striatal projections modulate striatal signaling, which is impaired in Huntington’s Disease (HD). Neurotrophic factor BDNF release from cortical afferences is decreased in cortico-striatal synapses as a consequence of Exp-HTT-mediated down-regulation of bdnf transcription and axonal transport in cortical neurons. A shift from synaptic to extrasynaptic NMDAR-dependent signaling participates to striatal neurons to death. In a physiological condition, calcium influx through synaptic NMDAR promotes activation of the MAPkinase/ERK signaling pathway along with its nuclear target, the MSK-1 protein, which phosphorylates the transcription factor CREB. MSK-1 activation promotes chromatin remodeling, which is crucial for CREB-mediated pgc-1α transcription, a key gene involved in mitochondria biogenesis. Synaptic NMDARs also promote formation of non-toxic Exp-HTT inclusion via TRIC. In HD, localization and activity of extrasynaptic NMDAR are enhanced by Exp-HTT, which promotes neuronal cell injury and death. The toxic effect of extrasynaptic NMDAR is partly due to (i) the upregulation of Rhes expression that disaggregates the non-toxic Exp-HTT inclusions (ii) to an impairment of mitochondrial functions and (iii) to a decrease of the ERK/MSK-1/CREB signaling module to the pgc-1α promoter. Dopamine release from nigro-striatal inputs promotes oxidative stress via the production of reactive oxygen species (ROS), which potentiates activation of the pro-apoptotic JNK pathway induced by Exp-HTT. In addition, Dopamine potentiates Exp-HTT-mediated striatal neurons death through activation of the Rho/ROCK signaling pathway downstream D2R.
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