101 © Springer International Publishing Switzerland 2015 U. Rüb et al., The Neuropathology of Huntington’s Disease: Classical Findings, Recent Developments and Correlation to Functional Neuroanatomy, Advances in Anatomy, Embryology and Cell Biology, Vol. 217, DOI 10.1007/978-3-319-19285-7_9 Chapter 9 The Disease Protein Huntingtin and Neuronal Protein Aggregations in Huntington’s Disease (HD) 9.1 The Disease Protein Huntingtin Identified in 1993 and located on chromosome 4p16.3, the human HD gene (also called IT15) contains 67 exons and spans more than 200 kb. It harbors meiotically unstable CAG trinucleotide or polyglutamine repeats (cytosine, adenine, guanine) in its exon 1, which encode the very large 350 kDa huntingtin protein ( Htt). Htt consists of about 3100 amino acids and undergoes extensive posttranslational modifications (Fig. 9.1) (Andrew et al. 1993; Atkin and Paulson 2014; Borrell-Pagès et al. 2006; Brundin et al. 2010; Cattaneo et al. 2005; Davies et al. 2007; Duyao et al. 1993; Finkbeiner and Mitra 2008; Imarisio et al. 2008; Labbadia and Morimoto 2013; Li and Conforti 2013; Li and Li 2011; Margolis and Ross 2003; Myers et al. 1991; Ortega et al. 2007; Paul 2008; Renner and Melki 2014; Schulte and Littleton 2011; The Huntington’s disease Collaborative Research Group 1993; Vonsattel 2008; Walker 2007a, b). In symptomatic HD patients and asymptomatic gene carriers, the CAG trinucleo- tide and the polyglutamine repeats are pathologically expanded and give rise to an elongated polyglutamine tract at the N-terminus of mutant Htt that confers the ten- dency to Htt to form intraneuronal inclusions (Fig. 9.1) (Andrew et al. 1993; Atkin and Paulson 2014; Borrell-Pagès et al. 2006; Cattaneo et al. 2005; Duyao et al. 1993; Finkbeiner and Mitra 2008; Gunawardena and Goldstein 2005; Imarisio et al. 2008; Labbadia and Morimoto 2013; Li and Conforti 2013; Li and Li 2011; Margolis and Ross 2003; Myers et al. 1991; Ortega et al. 2007; Paul 2008; Renner and Melki 2014; Schulte and Littleton 2011; The Huntington’s disease Collaborative Research Group 1993; Vonsattel 2008; Walker 2007a, b; Wooten et al. 2006). The normal physiological CAG repeat sequences comprise 6–35 CAG triplets, whereby sequences of 28 and more already behave unstable during meiosis and may be prone to potentially symptomatic mutations. CAG repeat sequences longer than 35 are considered pathologically expanded, 36–40 CAG repeats lead to an incomplete penetrance, and expansions of 41 or more CAG repeats lead to the fully developed