ReviewHuntington's disease: The current state of research with peripheral tissues
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.
References (157)
- et al.
Huntington's disease of the endocrine pancreas: insulin deficiency and diabetes mellitus due to impaired insulin gene expression
Neurobiol. Dis.
(2002) - et al.
Cellular immune responses in Huntington's disease (H.D.). Detection of H.D. and multiple sclerosis (M.S.) brain antigenicity by H.D. but not M.S. lymphocytes
Cell. Immunol.
(1977) Huntingtin aggregation and toxicity in Huntington's disease
Lancet
(2003)- et al.
Glutamate receptor abnormalities in the YAC128 transgenic mouse model of Huntington's disease
Neuroscience
(2007) - et al.
Magnetic resonance imaging as an approach towards identifying neuropathological biomarkers for Huntington's disease.
Brain Res. Rev.
(2008) Transcriptional dysregulation in Huntington's disease
Trends Neurosci.
(2000)Transcriptional signatures in Huntington's disease
Prog. Neurobiol.
(2007)- et al.
Increased oxidative damage and mitochondrial abnormalities in the peripheral blood of Huntington's disease patients
Biochem. Biophys. Res. Commun.
(2007) - et al.
Blood level of brain-derived neurotrophic factor mRNA is progressively reduced in rodent models of Huntington's disease: restoration by the neuroprotective compound CEP-1347
Mol. Cell. Neurosci.
(2008) - et al.
Transcriptional repression of PGC-1alpha by mutant huntingtin leads to mitochondrial dysfunction and neurodegeneration
Cell
(2006)