SCA1
Symptoms of spinocerebellar ataxia type 1 (SCA1) are not easily distinguishable from other ataxias. They include unsteady movements (ataxia), problems with speech (dysarthria) and problems with eye movements (opthalmoplegia) (Sasaki et al, 1996). However there is a characteristic delay in muscle activity following nerve stimulation (nerve to muscle conduction time) (Schöls at al, 1997). MRI brain scans of people with SCA1 and 2 show similar features. However, in SCA1 the degree of abnormality seen is directly related to the severity of the symptoms. Therefore brain scans could be used to monitor progression of the condition and measure the effectiveness of treatments (Guerrini et al, 2004).
In SCA1 the expanded trinucleotide repeat is increased from 6-39 repeats to 40-81 repeats (Chong 1995). Longer expansions are associated with a more severe condition and an earlier presentation of symptoms (Orr et al, 1993). The abnormality in SCA1 occurs within the gene which codes for the protein ataxin-1 (Banfi et al, 1994). This protein is found throughout the body, usually in the cell’s central body (nucleus) and in some cells in the cell fluid (cytoplasm) (Servadio et al, 1995).
The symptoms of SCA1 are thought to be caused by the toxic effects of the polyglutamine expansion in the ataxin-1 protein, which causes damage and death of nerve cells (Zoghbi & Orr, 2000). Research into the way in which the protein causes this damage is currently ongoing. Some suggestions of the mechanism are explained below.
The CAG expansion causes the protein to misfold which may lead to a lack of recognition by the cell’s normal mechanism for breaking down unwanted proteins, and thus increased amounts of the mutant protein will remain in the cell. In addition to this, the mutant protein is thought to prevent the proper working of the cell’s recognition/breakdown system itself, allowing other toxic proteins to remain (Park et al, 2005).
Polyglutamine expanded proteins are shown to interact abnormally with other proteins and disrupt tasks such as the regulation of gene expression (the process by which DNA gene codes are converted to proteins in the body) (Tsai et al, 2004). Normal ataxin-1 protein is involved in the regulation of gene transcription and it is thought that the mutated version may cause a down regulation of genes required for a variety of cellular processes (Lin et al, 2000).
In addition to the mutated protein causing damage, research suggests that the loss of the normal ataxin-1 may contribute to the condition. Loss of this protein has been shown to prevent the formation of useful protein complexes and hinder the control of calcium levels within the specialised cells in the area of the brain known as the cerebellum (Lim et al, 2008).
Research into possible treatments for SCA1 continues. One possibility being looked into is a way to prevent the protein misfolding in the first place. Chaperones are molecules which assist with protein folding and it is thought they could have a protective response by preventing the mutated ataxin-1 from clumping together and preventing its abnormal interaction with other non-toxic proteins (Sakahira et al, 2002). Indeed, when levels of chaperones were increased in mice with SCA1, some protection from neurodegeneration was seen (Cummings et al 2001).
Insulin-like growth factor (IGF-1) is a protein found throughout the body, including in the specialised cells of the cerebellum. It is important for cell maintenance and growth and there is evidence to support its protective role in SCA1 (Fernandez et al, 2005). Researchers are looking at this possibility in greater detail and IGF-1 given to mice with SCA1 was found to improve SCA1 symptoms (Vig et al 2006).
Finally, another possible therapeutic strategy for SCA1 is to modulate autophagy (the process by which cells digest damaged or unnecessary products) and assist with getting rid of mutant proteins. Evidence shows that this autophagy plays an essential role in the clearance of ataxin-1 from the cell fluid (cytoplasm) (Iwata et al, 2005). Some success in mouse models has been seen using a drug called rapamycin to induce autophagy and reduce toxicity of other polyglutamine proteins, suggesting that this approach may also help in SCA1 (Ravikumar et al, 2004).
Finally, there is also research going on to look at genetic approaches for SCA1; to read more about this see the box on the right hand side of this page.
REFERENCES
Banfi et al. Nat Gen, 1994; 7(4): 513-520
Chong et al. Nat Gen, 1995; 10(3): 344-350
Cummings et al. Hum Mol Genet, 2001; 10(14): 1511-15S18
Fernandez et al. Brain Res Brain Res Rev, 2005; 50: 134-141
Guerrini et al. Brain, 2004: 127(8): 1785-1795
Iwata et al. Proc Natl Acad Sci USA, 2005; 102(37): 13135-13140
Lim et al. Nature, 2008; 452(7188): 713-718
Lin et al. Nature Neuroscience 2000; 3(2): 157-163
McCampbell et al. Proc Natl Acad Sci USA 2001; 98(26): 15179-15184
Orr et al. Nat Gen, 1993; 4(3): 221-226
Park et al. Mol Cells, 2005; 19(1): 23-30
Ravikumar et al. Nature Genetic, 2004; 36(6): 585-595
Sakahira et al. Proc Natl Acad Sci USA, 2002; 99(4): 16412-16418
Sasaki et al. Acta Neurol Sand, 1996; 93(1): 64-71
Schöls at al. Annal Neurol, 1997; 42(6): 924-932
Servadio et al. Nat Gen, 1995; 10(1): 94-98
Steffan et al. Nature 2001; 413(6857): 691, 693-694
Tsai et al. Proc Natl Acad Sci USA, 2004; 101(12): 4047-4052
Vig et al. Brain Res Bull, 2006; 69(5):573-579
Zoghbi & Orr. Annual Review Neuroscience, 2000; 23: 217-247
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