Neurochemical Mechanisms in Disease P35 potx

Trinucleotide-Expansion Diseases 325 et al., 1998). The clinical phenotype is extremely variable and strong anticipation in subsequent generations is a feature of this disease. Myotonia and progressive muscle weakness are characteristics of the adult-onset disease. Developmental and mental abnormalities together with hypotonia and respiratory distress are characteristics of the more severe congenital disease. It has been suggested that the CTG expansion may alter DMPK protein levels by interfering with DMPK gene transcription, with RNA processing, and/or with translation. The results would be abnormal phosphorylation of downstream substrates (discussed by Cummings and Zoghbi, 2000). Other possibilities include alterations in expression of nearby genes or sequestra- tion of RNA-binding proteins leading to abnormal RNA processing (Cummings and Zoghbi, 2000). DM1 transcripts have been shown to accumulate in the nuclei of muscle cells (Jiang et al., 2004). DMPK mRNA is widely expressed in cortical and subcortical neurons and the mutant transcripts accumulate in discrete foci within the neuronal nuclei. Human EXP (expansion RNA-binding) proteins are homologous to muscleblind proteins that are critical for terminal differentiation of embryonic pha- ryngeal, visceral, and somatic muscle bodies, and for eye formation in Drosophila. In DM1, proteins in the muscleblind family are recruited to these foci in the nuclei depleting their levels in the cytosol (Jiang et al., 2004). Additionally, pre-mRNAs show abnormal regulation of alternative splicing. These findings suggest a toxic gain of function of DMPK mRNA, which may contribute to the muscle and neurological symptoms (Jiang et al., 2004; Lee and Cooper, 2009). 2.4 Friedreich Ataxia (FRDA) FRDA is the most common inherited ataxia with a prevalence of about 1 in 50,000 in the general population. FRDA is characterized by ataxia, dysarthria, diminished reflexes, cardiomyopathy, diabetes, and degeneration of spinal cord, dorsal root gan- glia, and several peripheral systems (Cummings and Zoghbi, 2000). The disease is inherited in an autosomal recessive fashion. The affected gene (X25; frataxin)is located at chromosome 9q13-q21.1. The mutation is due to an expansion of a GAA repeat in a noncoding region (intron 1) of a gene that codes for a highly conserved nuclear-encoded protein named frataxin that binds to the inner mitochondrial membrane (Dürr et al., 1996; Campuzano et al., 1996). The mutation appears to alter mRNA processing, resulting in low levels of frataxin. In normal individuals the GAA sequence is usually repeated 7–22 times, but in homozygous patients with Friedreich ataxia, the nucleotide repeat number may be 66–1700 (Sharma et al., 2004). Most Friedrich ataxia patients have expansions in both alleles. The longer the repeats, the lower the level of expressed frataxin and the more severe is the disease phenotype (Gatchel and Zoghbi, 2005). Two mild cases of Friedreich ataxia have been reported in heterozygotes for large expansions and an allele for a 44 and 66 triplet repeat, respectively. Due to somatic instability, 15% (GAA-44) and 75% (GAA-66) of cells contained alleles with ≥66 triplet repeats, suggesting a plausible mechanism for the mild phenotype. No such instability was noted in a sibling who 326 A.J.L. Cooper and J.P. Blass Fig. 1 Molecular and biochemical basis of Friedreich’s ataxia (FRDA). (a) A GAA-repeat expansion in the first intron of the FRDA gene results in decreased levels of frataxin as a result of inhibition of transcriptional elongation. (b) Alterations in mitochondrial biochemistry that are associated with reduced frataxin levels. Proposed functions for frataxin include iron binding, pro- tection and synthesis of Fe–S clusters, providing a binding partner for ferrochetalase in heme (haem) metabolism, and providing a metabolic switch between heme metabolism and Fe–S cluster biosynthesis. In FRDA, reduction of frataxin results in lowered levels of aconitase and respiratory complexes I, II, and III. Cytosolic proteins that contain Fe–S clusters may also be affected. Inability to form Fe–S clusters leads to an accumulation of iron, which leads to increased free radical formation (Fenton chemistry) in these organelles. Increased free radical formation may feed back to further decrease levels of Fe–S clusters, which are known to be sensitive to oxidative stress. Trinucleotide-Expansion Diseases 327 possessed an expanded GAA allele and a GAA-37 allele and was clinically normal (Sharma et al., 2004). Frataxin is normally targeted to mitochondria, and mitochondrial respiratory chain dysfunction, mitochondrial iron accumulation, and oxidative stress are important components of the FRDA disease mechanism. It is possible that frataxin is normally involved in mitochondrial iron metabolism, including the formation of iron–sulfur centers (Lane and Richardson, 2010). As discussed by Lane and Richardson (2010) the metabolic defect in FRDA leads to mitochondrial iron load- ing that results from dysregulation of mitochondrial iron metabolism/iron–sulfur cluster biosynthesis, heme biogenesis, and mitochondrial iron storage. Additionally, the abnormal mitochondrial iron deposits may promote Fenton chemistry (hydroxyl radical formation) and thus contribute to toxic free-radical production that compro- mises cellular dysfunction, eventually leading to cell death ( Pandolfo and Pastore, 2009). In FRDA patients with vitamin E and CoQ 10 deficiency, supplementation with these antioxidants appears to be beneficial to heart muscle mitochondria, and, to a lesser extent, skeletal muscle mitochondria. The antioxidant idebenone also appears to be beneficial to heart muscle in FRDA patients (reviewed by Cooper and Schapira, 2003). A mechanism, as proposed by Gatchel and Zoghbi (2005), linking mitochondrial biochemical defects to loss of frataxin is shown in Fig. 1. 2.5 Spinocerebellar Ataxia Type 8 (SCA8) SCA8 is a rare neurodegenerative disease caused by an expansion of a CTG repeat on chromosome 13q21 (Koob et al., 1999). The disease is characterized by progressive ataxia with cerebellar atrophy, decreased vibration sense, and brisk reflexes (Cummings and Zoghbi, 2000). The normal allele contains 15–50 triplet repeats. By contrast, 71–800 repeats have been observed in SCA8 patients. SCA8 is interesting because it shows a complex inheritance pattern with extremes of incomplete pene- tration, in which only one or two affected individuals are found in a given family (Ikeda et al., 2004). As noted above, SCA8 is unique among the trinucleotide repeat disorders in that the predicted gene product is not a protein, but rather is a noncoding RNA. It was suggested that the expressed RNA may be an antisense RNA that regulates the expression of other genes (Mutsuddi et al., 2004). Later it was found that the mutation produces toxic RNAs that alter RNA splicing activities of MBNL (Muscleblind-like) and CELF (CUGBP and ETR-3-like) proteins (Daughters et al., 2009).  Fig. 1 (continued) NFS1 is a gene that encodes mitochondrial cysteine desulfurase. This enzyme catalyzes the conversion of cysteine to alanine plus sulfane sulfur (S 0 ). The S 0 is incorporated into the Fe–S clusters. Isu1 is a gene that encodes a scaffold protein on which the Fe–S c lusters are assembled. ABCB7, ATP-binding cassette, sub-family B, member 7 (ABC transporter 7 protein); ISC, Fe–S cluster. From Gatchel and Zoghbi (2005) with permission 328 A.J.L. Cooper and J.P. Blass Interestingly, a small subset of patients with major psychoses, but without ataxia, appears to possess the SCA8 mutation (Vincent et al., 2000). Thus, additional genetic and/or environmental factors may play an important role in the expression of SCA 8 ataxia disease phenotype (Ikeda et al., 2004) or psychoses (Vincent et al., 2000). 2.6 Spinocerebellar Ataxia Type 12 (SCA12) This is an extremely rare disorder, characterized by a variety of abnormalities of movement as well as dementia in older subjects (Holmes et al., 1999).Thediseaseis caused by a CAG expansion in the UTR of the PPP2R2B gene (Holmes et al., 1999; Bahl et al., 2005). The expanded allele length ranges from 55 to 69 repeats. SCA12 is the only known disease caused by an expansion of a CAG repeat in a noncoding region of a gene. PPP2R2B encodes a brain-specific regulatory subunit (PR55β) of protein phosphatase 2A (PP2A). PP2A has been implicated in modulation of the cell cycle progression, tau phosphorylation, and apoptosis. Holmes et al. (1999) suggested that the CAG expansion may affect PR55β expression, perhaps by altering PP2A function in the brain. Interestingly, Holmes et al. (2003) suggested that the mutation might result in an overproduction of the PR55β mRNA. 3 Diseases Due to a Coding Trinucleotide Expansion—Polyglutamine (Q n )-Expansion Diseases Ten CAG-expansion diseases are currently known. In nine of these diseases (listed in Table 2), the mutation occurs in an exon (coding region) and results in an expansion of a Q n domain in the expressed protein. These nine diseases may therefore conveniently be referred to as Q n -expansion diseases. Some noncoding, non-CAG trinucleotide-expansion diseases may have expansions numbering in the thousands. By contrast, maximal expansions in the coding CAG-expansion diseases only occa- sionally exceed 100 trinucleotide repeats. In most cases, the protein is expressed normally, which suggests that the expanded Q n domain exerts a toxic gain of function to the mutated protein. Nevertheless, limited loss of function probably occurs in some cases, as discussed below. In general, all nine Q n -expansion diseases are characterized by progressive neuronal dysfunction, most often beginning in adult life. However, only selected neurons are affected. All the Q n -expansion diseases are characterized by protein aggregates in the affected regions, which may by cytosolic, nuclear, or both cytosolic and nuclear (Table 2). None of the mutated proteins in the CAG-expansion diseases are related, except for the possession of an expanded Q n domain. In every case, except SCA6, the mutated protein is widely expressed, not only throughout the brain, but also throughout the body. This wide expression raises important questions. What accounts for the restriction of the major disease phenotype to nervous tissue? And what accounts Trinucleotide-Expansion Diseases 329 Table 2 (CAG) n /Q n -expansion diseases a Disease Gene/Locus Affected Protein Normal Disease Aggregate Location Spinobulbar muscular atrophy (SBMA, Kennedy disease) AR Xq13-21 Androgen receptor (AR) 9–36 38–62 n,c Huntington disease (HD) Hd 4p16.3 Huntingtin 6–35 36–121 n,c Dentatorubralpallidoluysian atrophy (DRPLA, Haw River syndrome) DRPLA 12p13.31 Atrophin-1 6–35 49–88 n,c Spinocerebellar ataxia type 1 (SCA1) SCA1 6p23 Ataxin-1 6–44 b 39–82 n Spinocerebellar ataxia type 2 (SCA2) SCA2 12q24.1 Ataxin-2 15–31 36–63 c Spinocerebellar ataxia type 3 (SCA3, Machado–Joseph disease) SCA3 (MJD1) 14q32.1 Ataxin-3 12–40 c 45–84 n,c Spinocerebellar ataxia type 6 (SCA6) SCA6 (CACNA1A) 19p13 α 1A -Voltage-dependent channel subunit 4–18 21–33 c Spinocerebellar ataxia type 7 (SCA7) SCA7 13p12-13 Ataxin-7 4–35 37–460 n Spinocerebellar ataxia type 17 (SCA17) d SCA17 6q27 TATA-binding protein (TBP) 34≤43 45–55 n a From Cummings and Zoghbi (2000) updated to include Spinocerebellar ataxia type 17 and new information on CAG repeat size in some of the diseases. Subcellular location of brain protein aggregates typical of the Q n -expansion diseases are as follows: n, nuclear; c, cytosolic. b Alleles with 21 or more repeats are interrupted by 1–3 CAT trinucleotides; disease alleles contain pure CAG repeats. c There are occasional variant triplets at the third (CAA), fourth (AAG), and sixth (CAA) positions of the CAG repeat in the human gene (Limprasert et al., 1996). CAA is a redundant triplet code for glutamine. AAG codes for lysine. d The CAG stretch in the gene is interspersed with a few CAA trinucleotides. 330 A.J.L. Cooper and J.P. Blass for the often subtle differences in neuropathology among the different Q n -expansion diseases? In other words, by what mechanism does the selective vulnerability among the different Q n -expansion diseases occur? Finally, what mechanism can explain the incredibly sharp demarcation between pathological and nonpathological n values of n in the Q n domains? To date the literature is replete with studies characterizing Q n disease, particularly Huntington disease (HD). What follows is a brief description of the discovery of each Q n -expansion disease, and some key references, followed by a discus- sion of current theories on the mechanisms by which expanded Q n domains exert their neurotoxicity. Because of the huge volume of literature on Q n -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. 3.1 Spinobulbar Muscular Atrophy (SBMA; Kennedy Disease) Shortly after the discovery of the repeat disorder in FRAXA, it was shown that SBMA is caused by an expansion of a CAG repeat at chromosome Wq11-112 (La Spada et al., 1991, 1992). The mutation is caused by an expansion of a CAG repeat within the first exon of the AR gene coding for AR (the androgen receptor) (La Spada et al., 1991, 1992; Amato et al., 1993). Unlike all other known Q n -expansion diseases, which are inherited in an autosomal dominant fashion, SBMA inheritance is X-linked. Carrier females are usually clinically normal, although some may have mild symptoms. Affected males exhibit mild hypogonadism and gyneco- mastasia, although they are fertile. These features suggest mild loss of function in the affected gene. The main symptoms of SBMA are slowly progressive muscle weakness and atrophy of bulbar, facial, and limb muscles (Suzuki et al., 2009). The key histopathological findings of SBMA are an extensive loss of l ower motor neurons in the anterior horn of the spinal cord as well as in brainstem motor nuclei and intranuclear accumulations of mutant AR protein in the residual motor neurons (ARs are found on lower motor neurons as well as on other CNS neurons) (Suzuki et al., 2009). These findings suggest a toxic gain of function in the mutated SBMA. Androgens are important in regulating sexually dimorphic neurons in the rat brain. They are also important in signaling pathways in the motor neurons. As pointed out by Cary and La Spada (2008) a thorough understanding of androgen receptor signaling in motor neurons should provide important inroads toward the development of effective treatments for SBMA and a variety of other devas- tating motor neuron diseases. Suppression of disease progression by castration or by administration of leuprorelin acetate (a luteinizing hormone-releasing hormone antagonist) in a mouse model of SBMA has been reported (Suzuki et al., 2009). Some efficacy of leuporelin has also been demonstrated in a phase 2 clinical trial (Banno et al., 2009). Trinucleotide-Expansion Diseases 331 3.2 Huntington Disease (HD) In 1993, the Huntington Disease Collaborative Research Group reported that the mutation in HD is due to a CAG expansion in the gene at chromosome 4p16.3 (The Huntington Disease Collaborative Research Group, 1993). The affected protein, which contains an expanded Q n domain near the N-terminus, was named huntingtin (Htt). Htt is a large protein (M r ∼ 350,000). Homozygous Htt knock-out mice embryos die in utero, and it has been difficult to assign a biological function to Htt. Nevertheless, some evidence suggests that Htt may be an iron-regulated protein essential for normal nuclear and perinuclear organelles (Hilditch-Maguire et al., 2000). More recent evidence suggests a role in intracellular vesicular trafficking (Caviston and Holzbaur, 2009). HD is the most common of the (CAG) n /Q n - 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 100,000. In the United States i n the 1980s, it was estimated that 25,000 persons had HD (Conneally, 1984). HD is typically fully penetrant and is characterized by movement disorders (chorea), psychiatric and behavioral disorders, and cognitive decline. Symptoms usually begin in adulthood (∼30–40 years of age) and inex- orably worsen over a period of 10–25 years. In early onset cases (age <20; ∼5–10% of cases) survival time after onset is shorter and symptoms include rigidity, bradyki- nesia, and tremor. Seizures may also occur. The cause of death is related to debility and immobility, weight loss, and trouble swallowing. Pneumonia is the most common cause of death (Greenamyre and Shoulson, 1994). Some mild cortical atrophy may occur in end-stage disease, but the most striking change in brain morphology occurs in the caudate nucleus. The caudate may be reduced to a thin rim of tissue resulting in greatly enlarged ventricles. There is also atrophy of the putamen and globus pallidus. Microscopically, medium-sized spiny GABAergic projection neurons in the striatum are most vulnerable, whereas medium-sized and large aspiny interneurons are less affected (Greenamyre and Shoulson, 1994). Although fully penetrant, genetic and environmental factors may modulate the age of onset of HD (The US–Venezuela Collaborative Research Project and Wexler, 2004). 3.3 Spinocerebellar Ataxia Type 1 (SCA1) SCA1 is due to a (CAG) n expansion toward the N-terminus of the gene ATXN-1 that maps to chromosome 6p22-p23 and codes for the protein ataxin-1 (Orr et al., 1993; Zoghbi and Orr, 2009). The disease is characterized by degeneration of the cerebellum, spinal cord, and brainstem. The disease phenotype appears to be due to a toxic gain of function in the mutated protein and perhaps to some loss of function (Zoghbi and Orr, 2009). Protein aggregates are particularly prominent in the nuclei of Purkinje neurons. Ataxin-1 can be phosphorylated at serine 776. Mutation of this residue to an alanine greatly reduces the disease phenotype in CSA1 transgenic 332 A.J.L. Cooper and J.P. Blass mice, despite the fact that the mutated protein (with a Q 82 domain) accumulates in the Purkinje cell nuclei (Emamian et al., 2003). This finding suggests an effect of the expanded Q n domain on the properties of the protein at a residue (serine) distal to the mutation. Studies with DNA microarrays have suggested that the presence of the disease protein in SCA1-transgenic mice results in major changes in the expression of nine genes during disease progression. Interestingly, five of these genes centered on glutamate signaling in Purkinje cells (Serra et al., 2004). 3.4 Spinocerebellar Ataxia Type 2 (SCA 2) SCA2 is caused by a (CAG) n expansion in exon 1 of the ATXN2 gene (coding for the cytosolic protein ataxin 2 ( Atx2)) located in chromosome 12q24.1. Cerebellar Purkinje cells are targeted in this disease. Mutant Atx2-58Q, but not wild-type Atx2-22Q, specifically associates with the cytosolic C-terminal region of type 1 inositol 1,4,5-trisphosphate receptor (InsP(3)R1), an intracellular Ca 2+ release channel (Liu et al., 2009). The studies of Liu et al. (2009) suggest that disturbed Ca 2+ signaling may play an important role in SCA2 neuropathology. The authors suggested that the ryanodine receptor (RyanR) may be a potential therapeutic target to treat SCA2 patients. It is of interest that in a cohort of Central European subjects the n in the Q n domains of Atx2 was remarkably consistent. Q 22 represented 92% of the alleles and Q 23 represented 5–7% (Figueroa et al., 2009). The finding of such a con- stant number suggests evolutionary pressure to maintain this number in the Central European cohort. The finding with normal Atx2 contrasts with that noted for Htt, for example, where the wild-type (normal) Htt may have an n in the Q n domain ranging from 11 to 34 (Koroshetz and Martin, 1997). Recent studies suggest that an expansion of Q n domains in Atx2 beyond n = 22 may be associated with disruption of energy metabolism and severe obesity in some children (Figueroa et al., 2009). 3.5 Spinocerebellar Ataxia Type 3 (SCA3; Machado–Joseph Disease) SCA3 is characterized by progressive ataxia and external ophthalmoplegia. Recent studies have also suggested that auditory, vestibular, and ingestion-related dopamin- ergic and cholinergic systems may also be compromised (Rüb et al., 2008). Mental faculties in SCA3 patients usually remain intact. The disease phenotype is quite variable, but the major symptom with all patients is difficulty in walking. When the disease presents before age 20 it is usually characterized by marked spasticity, akinesia, and dystonia-like posturing. When the disease presents after age fifty, it is usually characterized by amyotrophic polyneuropathy, with fasciculations accompa- nying the ataxia. Other cases fall between the two (Uitti, 1994). The disease occurs in some families of Portuguese descent, and “hotspots” occur in Japan and parts of India. Trinucleotide-Expansion Diseases 333 The gene for SCA 3, which maps to chromosome 14q24.3-q32, was shown to be due to a CAG expansion in exon 10 and to a corresponding increase in the Q n domain in the affected protein (ataxin-3) (Kawaguchi et al., 1994). There are occasional variant triplets at the third (CAA), fourth (AAG), and sixth (CAA) positions of the CAG repeat in the human gene (Limprasert et al., 1996). The nucleotide fol- lowing the last trinucleotide in the CAG repeat in the human gene is a G in all cases studied where the number of CAG repeats is less than 20. In 55% of the genes containing a CAG repeat of between 27 and 40 trinucleotides, a C nucleotide followed t he CAG repeat; and in all cases of expanded (pathological) CAG repeats, a C nucleotide followed the CAG. The authors suggested that the C variant may be associated with CAG repeat instability (Limprasert et al., 1996). Ataxin-3 is a 42-kDa protein in which the Q n domain is positioned toward the C-terminus. The N-terminus, which is whimsically termed Josephin, is highly conserved from nema- todes to humans (Chow et al., 2004). There are two ubiquitin-binding sites between Josephin and the Q n domain. Josephin, which is globular and monomeric, possesses ubiquitin protease activity (Chow et al., 2004). The expanded Q n domain may desta- bilize the Josephin domain perhaps resulting in a loss of function (Chow et al., 2004). 3.6 Dentatorubral Pallidoluysian Atrophy (DRPLA; Haw River Syndrome) This disease, which is characterized by progressive ataxia, choreoathetosis, dystonia, seizures, myoclonus, and dementia, maps to chromosome 12p12-ter (Koide et al., 1994; Nagafuchi et al., 1994). The disease is fairly common in Japan, but very rare in Caucasians. The mutated protein, which has an M r of about 140,000, contains a Q n domain in the middle of the protein with a serine-rich region in front of this region (Margolis et al., 1996). The mutated protein was originally named atrophin, but is now named atrophin-1 because there is also another closely related protein in humans (atrophin-2). Evidence suggests that the two proteins may act as transcriptional corepressors during embryonic development (Zoltewicz et al., 2004). 3.7 Spinocerebellar Ataxia Type 6 (SCA 6) This disease is a late onset disorder of the cerebellum characterized by selective and progressive loss of Purkinje cells. Initially the disease was thought to be confined to the cerebellar cortex, dentate nucleus, and inferior olives, but more recent studies suggest more widespread cerebellar involvement (Seidel et al., 2009; Wang et al., 2010). The disease is caused by a CAG expansion in the SCA6 gene at chromosome 19p13, which codes for the α 1A -voltage-dependent calcium channel subunit (Zhuchenko et al., 1997). Six isoforms of this protein have been described. The CAG repeat is within the open reading frame and is predicted to encode Q n domains in 334 A.J.L. Cooper and J.P. Blass three of the isoforms (Zhuchenko et al., 1997). The protein is abundantly expressed in Purkinje cell bodies and dendrites (Restituito et al., 2000). The disease is unique among the Q n -expansion diseases in that the pathological number of repeats is much lower than in the other diseases in this group and the maximal expansion noted thus farissmall(Table2). Unlike the other diseases in this group, the affected protein in SCA6 is a membrane-spanning protein. The mutation apparently shifts the voltage dependence of channel activation and rate of inactivation, and impairs normal G-protein regulation of P/Q channels (Restituito et al., 2000). This may be r egarded as a loss of function. In addition, the mutated SCA6 may impair normal proteasome function (Seidel et al., 2009) and prevent cell death (Matsuyama et al., 2004). A point mutation in the SCA6 gene gives rise to a different disease phenotype, namely familial hemiplegic migraine (Ophoff et al., 1996). Inasmuch as patients with familial hemiplegic migraine do not exhibit cerebellar ataxia, the ataxia in SCA6 is presumably a pathological gain of function resulting from the Q n expansion. Thus, SCA6 seems to exhibit features of both loss and gain of function for the mutated protein. Two episodic ataxias have been described in the literature. It is now clear that episodic ataxia type 2 (EA2) is identical with SCA6. The other (EA1), which is characterized by attacks of generalized ataxia and by continuous myokymia (irregular twitching), is due to a point mutation in the voltage-gated potassium channel gene KCNA1 (Cusimano et al., 2004). Clearly, EA1 and EA2/SCA-6 are both examples of channelopathies. 3.8 Spinocerebellar Ataxia Type 7 (SCA7) SCA7 is characterized by late-onset neuronal loss in the cerebellum, brainstem, and retina (Miller et al., 2009). It is the only Q n -expansion disease in which the retina is affected. The disease is caused by a CAG expansion in the gene at chromosome 13p12-13 (David et al., 1997). The affected gene has an M r of about 100,000. Because the biological function of t he protein was unclear, it was initially named ataxin-7. The SCA7 gene product, ataxin-7, is now known to be a subunit of a transcriptional coactivator complex (STAGA or TFTC) that has histone acetyltrans- ferase activity (Helmlinger et al., 2004, 2006a, b). Thus, transcriptional regulation seems to be altered in SCA-7 (and possibly other Q n -expansion diseases). 3.9 Spinocerebellar Ataxia Type 17 (SCA17) This was the last of the SCAs to be shown to arise from a Q n expansion in the mutated protein. Koide et al. (1999) identified a CAG expansion in the transcription factor TATA-binding factor protein TBP gene in a patient with short stature, pyra- midal signs, and mental retardation. Since then this extremely rare disease has been identified in a few European and Japanese families (Rolfs et al., 2003). Cerebral . the disease protein in SCA1-transgenic mice results in major changes in the expression of nine genes during disease progression. Interestingly, five of these genes centered on glutamate signaling. findings suggest a toxic gain of function in the mutated SBMA. Androgens are important in regulating sexually dimorphic neurons in the rat brain. They are also important in signaling pathways in. of leuporelin has also been demonstrated in a phase 2 clinical trial (Banno et al., 2009). Trinucleotide-Expansion Diseases 331 3.2 Huntington Disease (HD) In 1993, the Huntington Disease Collaborative