Molecular mechanisms involved in the pathogenesis of Huntington Disease.

PERANDONES CLAUDIA; RADRIZZANI MARTIN; MICHELI FEDERICO

Nova Science Pub Inc.

Año: 2010 p. 40

978-1-617289-71-2

<!-- /* Font Definitions */ @font-face {font-family:"MS Mincho"; panose-1:2 2 6 9 4 2 5 8 3 4; mso-font-alt:"ＭＳ 明朝"; mso-font-charset:128; mso-generic-font-family:roman; mso-font-format:other; mso-font-pitch:fixed; mso-font-signature:1 134676480 16 0 131072 0;} @font-face {font-family:"@MS Mincho"; panose-1:0 0 0 0 0 0 0 0 0 0; mso-font-charset:128; mso-generic-font-family:roman; mso-font-format:other; mso-font-pitch:fixed; mso-font-signature:1 134676480 16 0 131072 0;} /* Style Definitions */ p.MsoNormal, li.MsoNormal, div.MsoNormal {mso-style-parent:""; margin:0cm; margin-bottom:.0001pt; mso-pagination:widow-orphan; font-size:12.0pt; font-family:"Times New Roman"; mso-fareast-font-family:"MS Mincho"; mso-ansi-language:EN-GB; mso-fareast-language:EN-US;} span.apple-style-span {mso-style-name:apple-style-span; font-family:"Times New Roman"; mso-bidi-font-family:"Times New Roman";} @page Section1 {size:612.0pt 792.0pt; margin:70.85pt 3.0cm 70.85pt 3.0cm; mso-header-margin:36.0pt; mso-footer-margin:36.0pt; mso-paper-source:0;} div.Section1 {page:Section1;} --> Huntington´s disease (HD) is an autosomal-dominant, progressive neurodegenerative disorder with a distinct phenotype, including chorea, incoordination, cognitive decline, and behavioral difficulties. The underlying genetic defect responsible for the disease is the expansion of a CAG repeat in the gene coding for the HD protein, huntingtin (htt). This CAG repeat is an unstable triplet repeat DNA sequence, and its length is inversely correlated with the age at onset of the disease. Expanded CAG repeats have been found in 8 other inherited neurodegenerative diseases. Despite its widespread distribution, mutant htt causes selective neurodegeneration, which occurs preferentially and most prominently in the striatum and deeper layers of the cortex. Remarkable progress has been made since the discovery of HD gene in 1993. Animal models to study the disease process, unraveling the expression and function of wild-type and mutant huntingtin (htt) proteins in the central and peripheral nervous systems, and understanding expanded CAG repeat containing mutant htt protein interactions with CNS proteins in the disease process have been developed htt may cause toxicity via a wide range of different mechanisms. The primary consequence of the mutation is to confer a toxic gain of function on the mutant protein and this may be modified by certain normal activities that are impaired by the mutation. It is likely that the toxicity of mutant htt is only revealed after a series of cleavage events leading to the production of N-terminal huntingtin fragment(s) containing the expanded polyglutamine tract. Although aggregation of the mutant protein is the hallmark of the disease, the role of aggregation is complex and the arguments for protective roles of inclusions are discussed. HD progression has been found to involve several pathomechanisms, including  expanded CAG repeat protein interaction with other CNS proteins, transcriptional dysregulation, calcium dyshomeostasis, defective mitochondrial bioenergetics and abnormal vesicle trafficking. Notably, not all the effects of mutant htt are cell-autonomous, and it is possible that abnormalities in neighboring neurons and glia may also have an impact on connected cells. The present review focuses on HD, outlining the effects of mutant htt in the nucleus and cytoplasm as well as the role of cell-cell interactions in the HD pathology. The widespread expression and localization of mutant htt and its interactions with a variety of proteins suggest that mutant htt engaged multiple pathogenic pathways. A better understanding of these mechanisms will lead to the development of more effective therapeutic targets.