Abnormal morphology of peripheral cell tissues from patients with Huntington disease

Abstract

We investigated the genotype-dependency of morphological abnormalities in peripheral cells from Huntington disease (HD) patients. Cell cultures derived from skin and muscle biopsies showed a different set of abnormalities depending on the genotype (i.e. heterozygous and homozygous for CAG mutations) and the tissue (i.e. fibroblasts and myoblasts). In general, homozygotes' cell lines showed massive ultrastructural damage of specific cell organelles compared with age matched control. These consist of vacuolization, deranged crests and matrix found within giant mitochondria. In addition, enlarged endoplasmic reticulum and the occurrence of numerous autophagic vacuoles, which were similar to those occurring in neurons within affected brain areas, were described. Despite a comparable dose-dependency on mitochondrial changes, this kind of alterations differ in fibroblasts compared with myoblasts. In fact, the internal mitochondrial structure was merely lost in myoblasts, while it shows pathological re-organization within fibroblasts, where altered crests appear as multilamellar circles. These data indicate that ultrastructural abnormalities from peripheral tissues of HD patients can be used as potential disease markers which are easier to get than autoptic brains. Moreover, the occurrence of ultrastructural cell pathology reminiscent of neuronal degeneration in HD, suggests the use of human peripheral cells as a tool to investigate the pathogenic cascade subsequent to huntingtin dysregulation.

Abnormal apocrine secretory cell mitochondria in a Huntington disease patient

“…In muscle biopsy specimens, for example, Arenas and colleagues [20] encountered enlarged mitochondria with disrupted cristae. Similar findings were evident in fibroblast and myoblast cell cultures made from biopsies of HD patients [21,22]. Ultrastructural study of lymphoblasts revealed major ultrastructural abnormalities present in approximately one-third of mitochondria from HD heterozygotes; homozygotes had an even higher fraction [23].…”

Genetics and Neuropathology of Huntington's Disease

“…In this study, not only the disease progression was more rapid in homozygous patients, but also homozygous patients appeared to have a wider spectrum of neurological symptoms. More recent work involving cell lines derived from heterozygous and homozygous HD patients (Mormone et al , 2006; Squitieri et al , 2010; Varani et al , 2003) and analyses of mouse models for HD (Fossale et al , 2002; Graham et al , 2006; Lin et al , 2001) also support the notion that HD is more severe in homozygosity. Thus, more recent work is consistent with the notion that, like other triplet repeat disorders, HD is not a true dominant disorder, and that gain of function is only one of the facets of this devastating disease.…”

An oxysterol biomarker for 7-dehydrocholesterol oxidation in cell/mouse models for Smith-Lemli-Opitz syndrome

“…Fibroblasts derived from human skin are used as cellular models to study the pathophysiology of a variety of disorders (28)(29)(30)(31), especially those involved in lipid metabolism (32)(33)(34). For example, fi broblasts from SLOS patients contain elevated levels of 7-DHC and these cells have been used to establish methods for 7-DHC analysis and to determine the biological effects of this lipid ( 32,33 ).…”