Abstract
Huntington's disease (HD) is a complex and severe disorder characterized by the gradual and the progressive loss of neurons, predominantly in the striatum, which leads to the typical motor and cognitive impairments associated with this pathology. HD is caused by a highly polymorphic CAG trinucleotide repeat expansion in the exon-1 of the gene encoding for huntingtin protein. Since the first discovery of the huntingtin gene, investigations with a consistent number of in-vitro and in-vivo models have provided insights into the toxic events related to the expression of the mutant protein. In this review, we will summarize the progress made in characterizing the signaling pathways that contribute to neuronal degeneration in HD. We will highlight the age-dependent loss of proteostasis that is primarily responsible for the formation of aggregates observed in HD patients. The most promising molecular targets for the development of pharmacological interventions will also be discussed.
Highlights
huntingtin gene (HTT) is ubiquitously expressed during embryonic development and at high levels in testis and in mature postmitotic neurons in adult human brain.[12]
Huntington’s disease (HD) is characterized by protein aggregates that accumulate within cells in a manner similar to that seen in various forms of spinocerebellar ataxia, as well as in other neurodegenerative disorders such as Alzheimer’s disease (AD) and Parkinson’s disease (PD)
As the full-length HTT is indispensable for manifestation of neuropathology clearly analogous to human HD,[28,29] the deposition of proteolytic products is not sufficient to initiate a toxic cycle leading to extensive neuronal damage in the striatum
Summary
HTT is susceptible to proteolysis by a number of proteases (Figure 1). Historically, HTT was initially identified as a caspase substrate and it was the first example of a protein associated with a neurodegenerative disorder cleaved during apoptosis.[39]. Calpains belong to the family of cysteine proteases typically activated by the elevation of intracellular Ca2 þ levels, either in response to plasma membrane depolarization or in response to Ca2 þ release from the intracellular stores.[44] In mice overexpressing mutant HTT, increased glutamate release from afferent neurons enhances NMDA-R activity. This leads to an intracellular Ca2 þ increase and activation of calpains, which in turn cleave the HTT protein into a series of proteolytic products[45] that promote NMDA-R-mediated excitotoxicity.[46] calpains can modulate HTT homeostasis via the catabolic process of autophagy. It has a primary role in the response to nutrient deprivation as it
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