Elsevier

Experimental Neurology

Volume 219, Issue 2, October 2009, Pages 385-397
Experimental Neurology

Review
Huntington's disease: The current state of research with peripheral tissues

https://doi.org/10.1016/j.expneurol.2009.05.012Get rights and content

Abstract

Huntington's disease (HD) is a genetically dominant condition caused by expanded CAG repeats. These repeats code for a glutamine tract in the HD gene product huntingtin (htt), which is a protein expressed in almost all tissues. Although most HD symptoms reflect preferential neuronal death in specific brain regions, even before the HD gene was identified numerous reports had described additional abnormalities in the peripheral tissues of HD patients, including weight loss, altered glucose homeostasis, and sub-cellular abnormalities in fibroblasts, lymphocytes and erythrocytes. Several years have elapsed since the HD mutation was discovered, and analyses of peripheral tissues from HD patients have helped to understand the molecular pathogenesis of the disease and revealed that the molecular mechanisms through which mutated htt leads to cell dysfunction are widely shared between central nervous system (CNS) and peripheral tissues. These studies show that in peripheral tissues, mutated htt causes accumulation of intracellular protein aggregates, impairment of energetic metabolism, transcriptional deregulation and hyperactivation of programmed cell-death mechanisms. Here, we review the current knowledge of peripheral tissue alterations in HD patients and in animal models of HD and focus on how this information can be used to identify potential therapeutic possibilities and biomarkers for disease progression.

Introduction

Huntington's disease (HD) is a devastating neurodegenerative disorder caused by an expansion of the CAG repeat in the IT-15 gene which codes for a protein named huntingtin (htt) (HDCRG, 1993). Htt, a very large protein that is highly conserved in vertebrates during evolution (Gissi et al., 2006), is ubiquitously expressed in human tissues, suggesting pivotal (yet still unidentified) roles in and outside the central nervous system (CNS). The pathological expansion of the polyglutamine (polyQ) tract results in mutant htt becoming cytotoxic in patients' brain tissues (especially in the basal ganglia and cortex), causing early dysfunction and progressive atrophy of these regions that results in chorea and other movement disorders associated with cognitive and behavioral symptoms. Although the neurological symptoms predominate, they are not the sole manifestation of HD. Early reports, before the discovery of the HD gene, described pathological phenotypes in peripheral tissues of HD patients, including weight loss (Sanberg et al., 1981, Djoussé et al., 2002, Hamilton et al., 2004, Aziz et al., 2009) and altered glucose homeostasis (Podolsky and Leopold, 1977; Podolsky et al.,1972). Other reported changes included sub-cellular abnormalities in fibroblasts (Menkes and Stein, 1973, Leonardi et al., 1978, Beverstock, 1984), lymphocytes (Pettegrew et al., 1981, McGovern and Webb, 1982) and erythrocytes (Pettegrew et al., 1980, Zanella et al., 1980) from HD patients. Growing evidence now suggests that cells from peripheral tissues of HD patients bear abnormalities related to the expression of mutant htt. These patients' peripheral cells therefore provide invaluable models for studying the molecular mechanisms through which endogenous htt leads to neuronal cell dysfunction.

This review focuses on current knowledge of peripheral tissue alterations in HD patients and in HD animal models. It also highlights how this information might be used to identify biomarkers for the progression of the disease as well as new therapeutic options.

Section snippets

Evidence for cardiac dysfunction in HD patients

From the clinical point of view, multiple epidemiological studies have shown that heart disease is the second leading cause of death in patients with HD (Chiu and Alexander, 1982, Lanska et al., 1988aLanska et al., 1988b, Sørensen and Fenger, 1992; Table 1A). These findings notwithstanding, heart disease has not been found to be more frequent in HD patients than in controls (Lanska et al., 1988a).

Another potentially important feature of heart disease in HD concerns altered autonomic system

Mutant htt and intracellular aggregate formation in peripheral tissues

A prominent feature of mutant htt is its tendency to form insoluble protein aggregates in vivo (Davies et al., 1997). Indeed, formation of htt protein aggregates in affected individuals' brains is the neuropathologic hallmark of HD (DiFiglia et al., 1997). PolyQ aggregates in HD show many of the attributes of amyloid fibrils, (Sugaya et al., 2007) given that htt aggregates form in several structural/molecular states, including nucleation of misfolded htt, (Sugaya et al., 2007) formation of

Conclusion

Current evidence, derived from intensive research efforts by many investigators over a long time-span, increasingly favors a widespread toxic effect of mutated htt in the peripheral tissues of patients with HD. But how can these observations help in the development of effective medications to slow or arrest the neurodegenerative process in HD? A drug discovery project needs to identify targets, defined as cellular components whose modulation is anticipated to have a therapeutic benefit for

Acknowledgments

The authors wish to thank patients and their families (Associazione Mauro Emolo O.N.L.U.S.) for their precious support. We also gratefully acknowledge Dr. Simonetta Sipione and two anonymous reviewers for their helpful comments on the manuscript.

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      These results suggest that mutant HTT gradually causes retinal dysfunction and degeneration (Table 10). Blood cells are among the most accessible cells in the organism, so the wide range of effects of pathogenic huntingtin on different blood cells such as erythrocytes and leukocytes has been extensively investigated (for a review of this work, see (Sassone et al., 2009)). Recently, microarray and RNA-seq analyses done from HD blood and brain samples have indicated that the gene expression changes induced in the brain by HTT-polyQ are similar to those found in blood cells, which suggests that the blood can be used to investigate HD in a non-invasive manner in humans (Mina et al., 2016; Moss et al., 2017) and monkeys (Clever et al., 2019).

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