Huntington's diseases (HD) is a devastating autosomal-dominant, progressive neurodegenerative disorder whose clinical characteristics includes progressive cognitive impairment, choreiform movement, dystonia, psychiatric disturbance and dementia. Pathologically, HD is characterized by a predominant loss of neurons in the striated and cortical areas of the brain with the formation of neuronal inclusions. ( Imarisio, S et al., 2008; Walker, F.O, 2007) This disorder had been previously reported, however the initial description of the disease was from that of George Huntington, a medical practitioner of Pomeroy, Ohio, in 1872. (G.Huntington, 1872) HD is categorized to be in the same family of neurodegenerative disease that is genetically distinct with a gain-of-function that is caused by CAG repeats mutation. This family of disease includes dentatorubralpallidoluysian atrophy (DRPLA), SBMA and spinocerebellar ataxia 1,2,3,6,7 and 17. (SCA1/2/3/6/7/17) (Zoghbi & Orr., 2000 ; Nakamura, K. et al., 2001) HD mutation is caused by expansion of CAG repeats of more than 36 in the first exon of huntingtin (Htt) gene on chromosome 4p16.3 (MIM ID *613004) which is translated into a polyglutamine (PolyQ) repeat near the amino terminus of Huntingtin protein which is a ubiquitously expressed ctyoplasmic protein. (The Huntington's Disease Collaborative Research Group, 1993) (Rubinsztein et al., 1996) studied a huge group of individuals whom carried 30 to 40 CAG repeats in their Htt Gene. Using the PCR method which allowed the examination of CAG repeats only, results show that individuals with 35 or fewer CAG repeats had no clinical manifestation of HD while most individual with 36 to 39 CAG repeats were clinically affected. Individuals with 35 CAG repeats show no penetrance of the disease whereas individuals with 36 to 39 shows incomplete penetrance. When the repeats reach above 40 or more the disease is fully penetrance. The length of the CAG repeats correlates inversely with the age of onset of HD. While juvenile HD (JHD) characterized with expansion of more than 60 repeats and an age of onset before 20 years old. JHD is usually inherited paternally. This review will discuss the role of Polyglutamine repeats in Huntington's disease which ranges from inheritances pattern, age of onset linking to CAG repeats and pathogenesis concept of HD.
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Huntington's Disease is one of the chronic neurodegenerative disorders that affect the central nervous system. (Gusella and Macdonald. 1995) Its classical signs are that of motor symptoms, cognitive symptoms, psychiatric symptoms (Kirkwood et al., 2001) and metabolic symptoms.(Van der Burg et al., 2009) It is found that movement difficulties are linked with both involuntary and voluntary movement, which conditions worsens progressively. One of the most common clinical manifestation of motor symptom is Chorea; jerky involuntary movement superimposed on a purposeful act. (Cummings JL, 1995) Severity of chorea increases during the initial years of HD but is later replaced by bradykinesia and rigidity (Craufurd, 1996). Patients develop rigidity as disease progresses, and its more common in Juvenile onset of HD. Behavior abnormalities comes along with personality changes, anxiety and irritability(James et al .,1994). At the end stage of HD, patient's mental capabilities become slower and dementia is being develop. This is usually characterized with poor concentration, inefficient use of memory and impairment of executive functions such as organizing, planning, checking and acquisition of new motor skills. (Craufurd, 1996; Rubinsztein et al., 2003)
Molecular genetics of Huntington's disease
The features of mutation in the HD gene elucidated many of the hallmarks of HD which includes the inverse relationship of age of onset correlating with the repeats length and Juvenile HD linkage to meiosis in spermatogenesis causing expansion in CAG repeats.(Myers et al., 1998; Patrick et al., 1999; Yvon et al., 1994) The Homo sapiens HD gene is located on the chromosome 4p16.3 by way of findings from linkage analysis followed by positional cloning in 1993. The HD gene is also known as IT-15 gene, consists of 67 exons. It encode for a protein of 350kda. With an increase expansion of the nucleic acids CAG in the coding region of the first exon coding region for the glutamine residues (polyQ) followed by two short stretches of prolines causes the disease.( The Huntington's Disease Collaborative Research Group, 1993) Normally the consecutive repeats of CAG that codes for glutamine in a healthy individual is repeated about 10-29 (median, 18). While on the other hand, HD patients have an increased in repeats number of 36 to 121 (median, 44). There are indications that length of the polyglutamine repeats sequence is inversely correlated with the age of disease onset. (Kremer et al., 1994) Another studies shows four CAG repeats size interval associated with varying disease risk in HD (Figure 1).; 1) Normal, 2) Meiotic instability range, 3) Reduced penetrance range and 4) Pathogenic range
Always on Time
Marked to Standard
Normal range is where alleles with 26 or less CAG repeats. This is not related to disease in any case and further adding on that these alleles have never been expanded and causes disease in the next generation.
Meiotic instability range is where alleles with 27-35 CAG repeats in HD gene which do not leads develop the disease. However theses alleles may show meiotic instability which may increase the number of repeats and causes disease in the next generation. (Telenius et al., 1995) An example would be a 27 CAG repeats in a healthy father has been reported to expand to 38 repeats in his diseased son (McGlennan et al., 1995)
Reduced Penetrance range or intermediate range is where only part of the individuals with 36-39 CAG repeats will develop HD. The repeats in this range do no show full penetrance (Rubinsztein et al., 1996). As the CAG repeats number increases, the penetrance also increases. This kind of reduced penetrance is an extreme case, which implies that genetic background like genetic modifier and environmental factors could be part of the disease onset.
Pathological range is individuals with more than 40 CAG repeats. These individuals will develop HD if they live long enough till the disease onset. There will be a higher chance of inheriting the disease to the next generation.
With the increase in CAG repeats expansion can cause earlier onset and progression of the disease. In comparison with patients with less CAG repeats expansion shows their first symptoms in the later part of their lives. The expanded CAG repeats encodes for a polyglutamine tract in the huntingtin protein which is widely expressed within the central nervous system and in extra-neural tissues. Huntingtin protein is expressed much more in neurons than in glial cells. With the accumulation of proteolytic huntingtin protein fragments and their aggregation will trigger a cascade that leads to increasing neuronal dysfunction through oxidative injury, transcriptional dysregulation, glutamate exitotoxicity (Jarabek et al., 2004;Li et al., 2003), apoptotic signals, mitochondrial dysfunction and energy depletion (Beal and Ferrante, 2004). However, these above changes are accompanied by neurochemical alterations also affect on other receptors, such as the dopamine (DA) and adenosine receptors involved in motor functions and not solely on glutamate receptors. (Ferre et al., 1993; Pavase et al., 2003; Teunissen et al., 2001)in the expression of the same mutation. ( Wells and Warren, 1998)
Figure 1. CAG Repeats size with association in Risk of Huntington's Disease. Adapted from ( Wells et al., 1998)
HD genes are highly unstable as CAG repeats shows expansion and contraction in number of repeats over generations. There are several factors which may affect the size and direction of the unstable repeats. The sex of the affected parent plays a part. As in maternal transmission, repeats on offspring shows nearly equal number or expansion and contraction are also observed. However in paternal transmission there are more frequent expansions and there is an increase in numbers of repeats. Furthermore meiotic instability and degree of instability have been described within somatic tissues of HD patients ( Telenius etal., 1994) Accounting for repeat instability there are three general mechanisms propose; 1) Misalignment with subsequent excision repair, 2) slippage during DNA replication and unequal crossover and 3) recombination Slippage-mediated length change during DNA replication. These could be use to better explain the increase in number of repeats in HD (Richards and Sutherland, 1994)
Age of onset
A strong inverse correlation between age of onset and CAG length have been review (Brinkman etal., 1997). The length of CAG repeats in the HD gene is said to be the most important factor affecting the age of onset which accounts for 70% of the variation in the age of onset (Andrew et al., 1993). However such broad range of onset can be link to number of CAG repeats, itself alone cannot be use to predict the age of disease onset (Sneel et al., 1993, Rubinsztein et al., 1996). A second factor which affects the age of onset is the sex of the parent. (Rubinsztein et al., 1996) shows that JHD patients are more likely to inherit the disease from their father and patient with late age of onset usually from their affected mother (Hall et al., 1983, farrer et al., 1992). Recent studies also shows that other genes also modify the age of onset in HD. For exaple In ( Elahe et al., 2009) shows linkage of PCG-1 alpha inhibition by mutant htt protein leading to transcriptional deregulation and mitochondrial dysfunction in HF. A polymorphism within intron 2 shows a statistically significant variability in the age of onset. It further suggests PGC-1 alpha has modifying effects on the pathogenic process of HD. (Rubinsztien et al., 1996) reported some HD patients with 36 repeats and some very old individuals with 36-39 repeats but have no recognizable HD symptoms which indicates that disease is not always fully penetrant. The definition of penetrance is the proportion of individuals with a specified genotype who present the expected phenotype in their expected lifespan. Thus the penetrance of HD increases with the number of repeats with 36-39 as intermediate range fig1 and above 40 repeats as complete penetrance. Due to expanded repeats sequences, repeats instability in HD has a distinct feature of genetic anticipation as symptoms appear at earlier ages with greater severity in next successive generation. Especially in paternal transmission, as it passes through the germ line, the repeats numbers increases and result in a much earlier age of onset of HD which can leads to JHD (Jennings, 1995)
Juvenile HD VS Classical HD
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Juvenile HD (JHD) is represented usually by a large expansion of beyond 60 CAG repeats with disease onset before 20 years old. (Harper,1991) studies show 70% to 80% of JHD is due to paternal transmission of expanded repeats. Large mutation repeats above 80 - 100 CAG repeats are rare and accounts for 5% of JHD cases ( Cannella et al., 2004) and may result infantile HD with disease onset 10 years earlier which has a particularly devastating progression rate (Squitieri et al., 2002, 2003b). Beside earlier onset, they also presented a peculiar phenotype which showcase learning problems, rigidity, dystonia and seizures (Nance et al., 1999; Cannella et al.,2004). JHD large expansion of CAG causes a gain of function and shows association in altered energy metabolism in peripheral tissues (Sawa et al., 1999 ; Lodi et al., 2000: Panov et al., 2002). An increase in protein
Neurological and psychiatric symptoms in Huntington's diseaseSymptoms manifested from adult and juvenile HDAdditional symptoms predominantly manifested in infantile HDBehavioral abnormalities
Depression and psychosis
Severe behavioral change
Seizures and myoclonic epilepsy
Predominant cerebellar features
SpasticityTable 1: Symptoms which may be shared by adult and juvenile HD patients are on the left side. On the other side are patients with unusual symptoms that are displayed in infantile HD and not in adult HD or Juvenile, HD. Table is adapted from (F. Squitieri et al., 2006)
aggregates accumulating in neuron is also present (Scherzinger et al., 1999).
Classical HD exhibit atypical motor symptoms (Squitieri et al., 2000a) yet usually without manifestation of chorea, bradykinesia, cerebellar features or rigidity. However in JHD, rigidity occurs more frequently and is associated with a widespread brain atrophy (Squitieri et al., 2000a). Despite the age of onset and differences in symptoms, an overlap set of common symptoms at onset between classical adult HD and JHD does exist in Table 1. In the case of infantile HD where CAG repeats are more than 80 - 90, contribute to a phenotype which clinical features are very different from classical HD and early onset of HD. This suggests additional pathogenic mechanisms are involved in cases of infantile HD which causes it to be more severe.
Genetic factors play a part in influencing JHD. The negative correlation of age of onset and number of CAG repeats has been widely reported (Guseella and McDonalds, 2002). There are many studies which shows a stringent linear correlation between repeats of more than 60 and age of onset, suggesting that JHD is much more dependent on lengths of repeats than classical HD (Telenius et al., 1993). However certain studies take account of young patients with more than 60 repeats but very often less than high repeats number of 80-90 CAG repeats. Such barrier occurs because of the rarity of such patients with infantile onset which are usually publish as single reports(Nance, 1997; Sue et al., 1998; Nance et al., 1999; Rasmussen et al., 2000; Squitieri et al., 2000b, 2003b; Gambardella et al., 2001; Landau and Cannard, 2003; Cannella et al., 2004; Duesterhus et al., 2004; Seneca et al., 2004; Schapiro et al., 2004; Ullrich et al., 2004) put the above studies together, of patients with high repeats number, it shows a reduced correlation between number of repeats and age of onset.
The pathogenesis of HD have yet to be fully elucidated, however there are emerging concepts on the pathogenesis of the disease; 1) Proteolytic Cleavage, 2) Conformational changes, 3) Transcription 4) Metabolism and mitochondrial Dysfunction, 5) Proteotoxic Stress, 6) Aggregation and inclusion formation, 7) Alteration of normal protein function
1) Proteolytic Cleavage
Several studies have indicate clear links of proteolytic cleavage which frees toxic CAG polyglutamine- containing fragments (Li et al., 2007 ). In (Wellington et al., 1998, 2002) studies of full length HD mouse models, models are created with a 6 caspase cleavage site in the huntingtin (htt) protein, results show that the pathogenic phenotype was attenuated in the models (Graham et al., 2006). Possibilities of multiple cleavage events might result in a variety of toxic fragments still remain (Hoffner et al., 2005).
Question from this concept would it be a single protease which is responsible to initiate the pathogenesis of HD or a variety of events?
2) Conformation changes
A protein with an expanded CAG polyglutamine is prone to aggregation in-vitro (Sherzinger et al., 1997), which may cause the transition to a novel and toxic conformation Schaffer et al., 2004; Nagai et al., 2007). Aggregation conformation is not an end consequence of a protein with polyglutamine tract as the aggregation conformation may differ for cell to cell environment. In (Diamond et al., 2000) studies a change in conformation in a expanded htt peptide was found it the next subsequent aggregation in vitro (Schaffer et al., 2004) In a separate study (Nagai et al., 2007) which demonstrate 2 conformational changes which result from
Figure 2. Pathogenesis of HD and different drug targets. Adapted from (Puneet et al., 2010)
the fusion of an expanded polyglutamine tract to thioredoxin (Nagai et al., 2007). After protein purification it conforms to an alpha-helical state however after a few days it conforms to a beta-sheet rich conformation. This beta sheet rich conformation is much more prone to aggregation and causes toxicity to cell when microinject into cultured cells ( Nagai et al., 2007). In contrast a polyglutamine-binding peptide (QBP1) is found to prevent the toxic conformation transition (Nagai et al., 2007). With the above information from studies it indicates that polyglutamine tract in protein may facilitates conformation changes which in return can impact numbers of factors and protein-protein interaction.
It is suggested that protein with glutamine tracts may interrupt with specific transcriptional factors that may disrupt gene expression which may leads to neurodegeneration. Study of (Okazawa, 2003) shows that interaction of such protein and transcriptional and co-factors may lead recruitment into aggregate. Transcription factors and co-factors like CREB-binding protein (CBP) and SP1. SP1 is link with soluble form of htt protein and interaction causes a repression of SP1 transcription activities due to polyglutamine tract (Li et al., 2002 ; Dunah et al., 2002). Further more it is found that mutant htt protein reduced the cytoplasmic interaction with repressor element-1 transcription factor/neuron restrictive silencer factor (REST/NRSF) which leads to nuclear enrichment of REST/NRSF, its enhanced binding to the neuron restrictive silencer element, and transcriptional repression of the gene encoding brain-derived neurotrophic factor (BDNF) (Zuccato et al., 2003). Recent work also suggests that soluble mutant htt protein selectively represses the transcription of PGC-1a, a regulator of essential mitochondrial genes, via interfering with the CREB/TAF4-dependent transcriptional pathway (Cui et al.,2006). CBP is also known to be found in nuclear inclusion formed by mutant htt protien (Nucifora et al., 2001)
4) Metabolism and mitochondrial dysfunction
It is still yet fully elucidated if mitochondrial deficits are specific to HD as patient with HD shows metabolic defects (Jenkins et al., 1993) which are described by weight loss despite having calories intake and nutrients (Djousse et al., 2002). Mutant htt protein may have several effects on mitochondria function.(Lin and Beal, 2006; Browne and Beal, 2004,2006) (Sawa et al., 1999; Panov et al., 2002; Yu et al., 2003) shows increased mitochondrial depolarization and early calcium defect in patients and mouse models. This may be due direct binding of mutant htt protein to mitochondria itself. However (Cui et al., 2006; Weydt et al., 2006) propose that indirect effect by way of the transcriptional repression of PGC-1alpha, which is a transcriptional co-activator that regulates mitochondria biogenesis and respiration.
5) Proteotoxic Stress
The pathogenic polyglutamine tract in mutant htt protein causes human disease which is closely similar to that of polyglutamine proteins to aggregate in vitro (Scherzinger et al., 1997). A key role in HD pathogenesis is protein misfolding. (Muchowski and Wacker, 2005; Rubinsztien et al., 2007; Ross and Pickart et al., 2004). It is also shown that the brain is more susceptible to protein misfolding as HD is associated with large intracellular inclusion and protein quality control worse as with age which is also a factor of HD onset (Zhou et al., 2003; Soti and Csermely, 2002). In (Ravikumar et al., 2002,2004 ; Berger et al., 2006) had describe autophagy as a process where cells can degrade aggregated proteins, the process had been implicated to be resistance to polyglutamine pathology in cells in Drosophila and mice studies. Further in (Hara et al., 2006; Komatsu et al., 2006) proof that loss of autophagy function induces neurodegeneration in mouse models and leads to accumulation of misfolded proteins. On the similar topic, (Bence et al., 2001) also shows that proteasome dysfunction has been link to polyglutamine pathogenesis. The study demonstrated that cultured cells with large intracellular inclusion formed by mutant htt protein are associated with proteasome impairment. These not only indicate proteasome blockage underlies impairment but also inability of proteasome to fully digest soluble expanded polyglutamine protein and generation of such proteins (Venkatraman et al., 2004; Holmber et al., 2004).
6) Aggregation vs. inclusion formation
7) Alteration of normal protein function
HD is dominantly inherited with a gain of function due to toxic activity of polyglutamine expanded proteins responsible for its pathogenesis. (Dragatsis et al., 2000) propose that that HD dominant might come to light in the knowledge of normal CAG repeats function. as it shows that normal htt protein inactivation leads to progressive neurodegeneration and htt protein function is essential for neurogenesis and postnatal development (Duyao et al 1995; White et al 1997; Zeitlin et al 1995). (Wexler et al., 1987) also shown that homozygous HD patient has similar disease severity and age of onset comparing to heterozygote patients which in turn rule out the loss of function as the main mechanism behind HD.
Disease study models.