Does loss of the normal protein function contribute to the pathogenesis of Huntington's disease?

BioscienceHorizons Volume 8 2015  10.1093/biohorizons/hzv005 Review article Does loss of the normal protein function contribute to the pathogenesis of Huntington’s disease? Heidi Paine* *Corresponding author: St Mary’s Hospital, Praed Street, London W2 1NY, England. Email: Supervisor: Nigel Hooper, Institute of Brain, Behaviour and Mental Health, Faculty of Medical and Human Sciences, University of Manchester, Manchester, M13 9PT, England. Neurodegenerative disorders such as Huntington’s, Alzheimer’s, Parkinson’s and prion diseases are progressive and without a cure. A common finding is one of misfolded protein aggregates, conventionally believed to underlie pathogenesis via a toxic gain of function. Recently, a potential contribution of loss of normal protein function has come under the spotlight. With a focus on huntingtin, the protein involved in Huntington’s disease, this review examines the evidence for the conventional ‘gain of function’ model, before considering the hypothesis that a loss of function contributes to pathogenesis. In support of a primarily toxic gain of function are findings that huntingtin aggregates are neurotoxic in vitro. Additionally, aggregates of mutant huntingtin proteins have been detected prior to neuropathological changes, supporting a causal role. However, a dissociation between the neurons containing mutant huntingtin aggregates and those that are most vulnerable in Huntington’s disease indicates the possibility of a contribution from a loss of protein function. Evidence suggests a neuroprotective role for huntingtin; loss of its functions could feasibly lead to neurodegeneration. An exclusive role of loss of function is contradicted by the finding that genetic ablation of huntingtin protein does not cause Huntington’s disease, but a contribution from loss of function is supported by similarities between neuropathological and behavioural phenotypes in animal models of Huntington’s Disease and those produced by loss of the normal functions of huntingtin. Perhaps, therefore, both loss and gain of function are necessary processes in Huntington’s pathogenesis, with neither one sufficient to cause the disease alone. Review of the current evidence fails to elucidate an exact role for loss of function in Huntington’s disease pathogenesis. More information is required on the extent to which depletion of the normal protein causes, rather than accompanies, disease. In the meantime, attempts at drug discovery should be mindful of the possibility of a contribution from loss of function when designing treatments and interpreting trial results. Key words: Huntington’s disease, huntingtin, neurodegenerative, striatal neurons, gain of function, loss of function Submitted on 4 January 2015; accepted on 22 July 2015 Introduction Neurodegenerative disorders, which affect the central nervous system, include Alzheimer’s, Parkinson’s and Huntington’s diseases (HDs), amyotrophic lateral sclerosis and the prion diseases. They can be inherited or sporadic, with infectious forms additionally seen in prion disease. Though aetiology and pathogenesis of each disease differs, a common feature is death of a cell population; the location or function of this population impacts upon phenotype. Because neurons are not a dividing cell population, those lost in disease cannot be renewed or replaced. These disorders are therefore progressive and currently have no cure. A finding common to many of these diseases is that of misfolded protein aggregates (Taylor, Hardy and Fischbeck, © The Author 2015. Published by Oxford University Press. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited. 1 Faculty of Biological Sciences, University of Leeds, Leeds LS2 9JT, England Review article Secondly, is the disease exclusively caused by a gain of function or does a loss of the normal protein function contribute? The latter would certainly help to explain the failure of some drugs to show efficacy in trials. Research has therefore seen a shift towards the identification of the normal protein functions and whether their loss contributes to, or is purely a secondary finding of, neurodegenerative diseases. With particular focus on HD, this work will discuss the normal protein functions before examining the hypothesis that a loss of the normal protein function contributes to the disease process. Also considered in this work are the subsequent implications of this upon current and future therapeutic avenues. Huntington’s disease HD is the most common polyglutamine neurodegenerative disorder, with a worldwide prevalence of 5 in 100 000 (Kumar and Clark, 2009, p. 1149). Most cases show classical autosomal dominant inheritance, with ∼3% due to de novo mutations. HD is caused by a mutation in the Huntingtin gene on chromosome 4, which codes for huntingtin protein (htt). The mutation is a dynamic CAG repeat expansion in the coding region of the gene causing expansion of the N-terminus of the huntingtin protein, with 41 or greater CAG repeats seen in affected individuals. HD shows anticipation, whereby age of onset decreases between generations. This is due to meiotic instability, which causes an increase in the number of CAG repeats. The clinical features typically manifest around the fourth decade, beginning with memory loss, personality changes and chorea. Bradykinesia and rigidity occur later, and cognitive impairment progresses to dementia. Death usually occurs within 15–20 years of symptom onset, often as a consequence of heart failure or aspiration pneumonia (Gil and Rego, 2008). Gross atrophy of the striatum is commonly cited as the pathological hallmark of HD. The most severely afflicted neurons are the GABAergic medium-sized spiny striatal neurons, which constitute around 95% of the striatal neuronal population. Specific subpopulations of striatal neurons are affected at different stages of disease, which is reflected by the temporal cascade of symptoms. Current therapies provide only symptomatic relief, and despite improving quality of life, they fall short of halting or reversing the disease. Huntingtin protein (htt) Huntingtin protein (Fig. 1) is ubiquitously expressed, but its concentration is highest in the central nervous system and the testes. Huntingtin in development Huntingtin is critical for embryonic development in mice, and generation of nullizygous huntingtin mice (Hdh−/−) causes embryonic death between Day 8.5 and 10.5 (Zeitlin et al., 1995). However, the same study found that mice heterozygous for the null mutation did not die during embryogenesis and were histopathologically and phenotypically indistinguishable Figure 1. Schematic diagram of huntingtin protein. The polyglutamine repeat region begins at amino acid 18, spaning up (...truncated)