Huntington's Disease as Neurodevelopmental Disorder: Altered Chromatin Regulation, Coding, and Non-Coding RNA Transcription.

Emanuela Kerschbamer,Marta Biagioli

doi:10.3389/fnins.2015.00509

Emanuela Kerschbamer, Marta Biagioli

Open Access

https://doi.org/10.3389/fnins.2015.00509

Copy DOI

Journal: Frontiers in neuroscience	Publication Date: Jan 13, 2016
Citations: 31	License type: cc-by

Affiliation: University of Trento

Abstract

Huntington's disease (HD) is a monogenic autosomal dominant, fatal disorder due to CAG trinucleotide expansion in exon 1 of the HD gene (HTT) (The Huntington's Disease Collaborative Research Group, 1993; Figure Figure1A).1A). Nowadays, there is no cure or effective treatment for the disease which presents with motor, cognitive and psychiatric dysfunction. Although typically conceived as a “neurodegenerative disease,” mainly affecting the GABAergic medium-sized spiny neurons (MSN) of the striatum and deep layers of the cortex (Rosas et al., 2003), an increasing body of evidence has surfaced indicating that abnormal neurodevelopment might also have a crucial role in HD (Mehler and Gokhan, 2000, 2001; Humbert, 2010). Neurodegenerative diseases have been classically defined as chronic and progressive disorders of the nervous system affecting neurologic and behavioral functions, which start with specific biochemical changes that ultimately lead to distinct histopathologic and clinical syndromes. On the contrary, neurodevelopmental disorders result from an anomaly of brain maturation, during fetal or early postnatal life, which is postulated to alter the structure and/or function of neuronal and synaptic populations (Harrison, 1995).

Highlights

Edited by: Owen Murray Rennert, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, USA
Typically conceived as a “neurodegenerative disease,” mainly affecting the GABAergic medium-sized spiny neurons (MSN) of the striatum and deep layers of the cortex (Rosas et al, 2003), an increasing body of evidence has surfaced indicating that abnormal neurodevelopment might have a crucial role in Huntington’s disease (HD) (Mehler and Gokhan, 2000, 2001; Humbert, 2010)
Additional consistent observations emerged from studies using mouse embryonic stem cells and neural committed progenitors bearing Htt CAG-expansion mutations (Jacobsen et al, 2011; Conforti et al, 2013; Biagioli et al, 2015) as well as patient-derived induced pluripotent stem cells (The HD iPSC Consortium, 2012), showing measurable molecular differences and a series of expanded CAG-associated phenotypes that point toward a central role of wild-type and mutant huntingtin in signal transduction, axonal guidance, synaptic transmission and neurodevelopment

Summary

Introduction

Further indications come from studies of mouse models with inactivation of the HD orthologue gene Htt. Huntingtin protein, is expressed in all cell types of the body, at all developmental stages and it has crucial roles during development and neurogenesis (Figure 1B). Given this key role of wild-type huntingtin during development, it is not surprising that studies on genetic engineered mice expressing Htt CAG-expansion pathogenic mutations show subtle molecular and structural deficits that portend altered developmental processes and precede the occurrence of neurological symptoms and signs of cell death (Luthi-Carter et al, 2000; Wheeler et al, 2000; Fossale et al, 2011).

Results

Conclusion