Mglur5: a Potential Target for the Treatment of Huntington's Disease

Abstract

ISSN 1479-6708 Future Neurology (2014) 9(3), 289–293 Huntington’s disease Huntington’s disease (HD) is a progressive neurodegenerative disorder with an age of onset between 35 and 50 years. At first, HD patients experience chorea and psychiatric alterations, associated with intellectual decline and inevitable death within 15–20 years [1,2]. HD is caused by a polyglutamine expansion in the amino terminus of the htt protein [3]. The length of the polyglutamine repeat inversely correlates with the age of disease onset and directly correlates with the severity of symptoms [4]. Pathological analyses of HD-affected brains has revealed neuronal loss of the GABAergic medium-sized spiny neurons (MSN) present in the striatum [5]. Although it is well established that the htt polyglutamine expansion is the cause of HD, it is unknown why this ubiquitously expressed mutant protein selectively results in the loss of MSNs. Moreover, it remains unclear whether HD occurs as the consequence of either the loss of normal htt protein or as a toxic gain of function due to the polyglutamine expanded form of the protein. Wild-type htt protein is both antiapoptotic [6] and essential for normal embryonic development [7,8]. Nevertheless, the resulting polyglutamine stretch confers neurotoxic functions of the htt protein, resulting in the activation of cell signaling pathways involved in neuronal dysfunction as a consequence of increased oxidative stress, gene transcriptional alterations, glutamate excitotoxicity, apoptosis, mitochondrial dysregulation and energy depletion [9–11]. Cleavage of the mutant htt amino-terminal region results in the generation of insoluble nuclear aggregates, which are suggested to play a key role in HD-related neuronal cell death. Notably, HD symptom severity is strongly correlated with htt aggregate formation and loss of striatal neurons [12]. Htt aggregates and inclusions are found first in the striatum and, over time, in the rest of the basal ganglia, followed by progressive localization throughout the substantia nigra and cortex. It is not known whether htt aggregates and inclusions are toxic as other evidences suggest that htt nuclear inclusions may be neuroprotective for MSNs [13,14].