A„-expansion diseases

Polyalanine (A ) expansions also give rise to disease phenotypes (Section 5). In eight of these diseases, the expansion is in a transcription factor and the disease phenotype is evident at birth. If transcription factor dysfunction contributes to Q -expansion diseases, then a hypothesis explaining the disease phenotype must account for the fact that the disease phenotype is present at birth in the A -expansion diseases, but is typically adult onset in Q -expansion diseases. 

Diseases Due to a Coding Trinucleotide Expansion—Polyalanine (A )-Expansion Diseases... 

Much of the following discussion on A -expansion diseases is from excellent reviews by Brown and Brown (2004) and Messaed and Rouleau (2009). Nine diseases are currently known to be associated with an expansion of an A domain in the affected protein (Table 3). Synpolydactyly type 11 (SPD), cleidocranial dysplasia... 

The inadequacy or nonexistence of health tools to combat tropical diseases is a key factor preventing effective control efforts. This was not always the case. During the first part of the twentieth century, tropical diseases were a concern of European colonial administrators because of their impact on territorial expansion diseases such as river blindness, sleeping sickness, and malaria incapacitated workers and limited exploitation of natural resources. This led to the establishment of the study of tropical medicine and the development of the European drug industry. But, as western interests withdrew, so did concern for tropical disease control (Janssens, Kivits, and Vuylsteke 1992). 

To date the literature is replete with smdies characterizing Q disease, particularly Huntington disease (HD). What follows is a brief description of the discovery of each Q -expansion disease, and some key references, followed by a discussion of current theories on the mechanisms by which expanded Qn domains exert their neurotoxicity. Because of the huge volume of literature on Q/,-expansion diseases, we have had to be selective in the references quoted. The diseases are listed in approximately the chronological order in which the mutation was discovered. 

More recent evidence suggests a role in intracellular vesicular trafficking (Caviston and Holzbaur, 2009). HD is the most common of the (CAG)n/Qn-expansion diseases, despite the fact that new expansion mutational expansions in the Htt gene are believed to be exceedingly rare. The incidence of HD worldwide is about 5-10 per 100,000 individuals. Japan has a very low rate (0.1-0.5 per 100,000), whereas in the Lake Maracaibo region of Venezuela the incidence exceeds 100 per... 

Although the expanded Qn domains impart a toxic gain of function, this does not explain the selective vulnerability in the various Q/j-expansion diseases. In all cases, the mutated Q domain is expressed throughout the brain. Therefore, the selective vulnerability must reside in a toxic gain of function that somehow involves the non-mutated part of the protein (Cummings and Zoghbi, 2001 Zoghbi and Orr, 2009). 

A characteristic feature of all the Q -expansion diseases is the presence of insoluble protein aggregates (inclusion bodies) in the affected brain regions. Some authors have suggested that these insoluble aggregates are toxic and thereby contribute to the disease process (e.g., Bates, 2003). However, other studies indicate that the insoluble aggregates per se may not be toxic (e.g., Saudou et al., 1998 Kuemmerle... 

Most probably, the aggregates in the Q -expansion disease are formed by a combination of (a) noncovalent ordered interactions (polar zippers), (b) noncova-lent interactions of disordered misfolded proteins, and (c) covalent modifications (TG-catalyzed cross-linking). 

Moreover, it was shown that mutant Htt in a mouse model of HD facilitates CRE-dependent transcription (Obrietan and Hoyt, 2004). Thus, mutated Htt may cause either increases (Obrietan and Hoyt, 2004) or decreases (Zuccato et al., 2003) in transcriptional regulation. Such alterations may contribute to the pathological response in HD and other CAG-expansion diseases. A particularly intriguing Qn-containing protein is PQBP-1, which binds to both Qn expansions and to brain-specific transcription factor Brn-2 (Waragai et al., 1999). Thus, aberrant interactions between an expanded Q domain and PQBP-1 may, in turn, result in aberrant transcription of Brn-2 and neuropathology. 

Glutamine-rich transcription factor Spl is readily cross-linked by TG 2 (Han and Park, 2000). Inasmuch as some TG 2 is present in the nucleus, and Qn domains are excellent substrates, it is possible that TGs may modulate the activity of at least some transcription factors in vivo. Because TG activity is increased in HD brain, and because the expanded Qn domain of Htt is an excellent TG substrate, the possibility exists that TGs play a critical role in altered transcription level and properties in Q -expansion diseases. 

A summary of many of the pathological mechanisms postulated to occur in Qn-expansion diseases and how they might be interrelated is shown in Fig. 2 (Steps... 

---