Research into other ataxias

SPINOCEREBELLAR ATAXIAS

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The spinocerebellar ataxias (SCAs) are a group of genetically inherited, progressive neurological disorders. There are currently 29 known SCAs; SCAs 1 – 8 and 10 – 30 (the term SCA9 has been reserved, but there is currently no condition associated with it). Each SCA is caused by a distinct genetic mutation, that is a defect in the genetic code, and as a result clinical symptoms differ between the disorders. All of the SCAs are inherited in a dominant fashion, meaning that only one copy of the defective gene needs to be passed on from parent to child for that chid inherit the disease.

The SCAs share some underlying similarities so research into one condition may deepen our understanding of other types of SCA too, and consequently there is some overlap in the summaries. This page provides summaries of current knowledge on the spinocerebellar ataxias type 1, 2, 3, 6, 7, and 17, which are the most common forms of SCA and account for over 50% of affected families world-wide. These 6 SCAs are all caused by the same kind of genetic defect; polyglutamine repeat expansion. Glutamine is an amino acid whose genetic code is the trinucleotide CAG. Repeats of the CAG trinucleotide can be found in the DNA of healthy individuals, but extended repeats of the CAG trinucleotide can cause disease. In SCAs 1, 2, 3, 6, 7 and 17, expanded CAG repeats are found within regions of the DNA that code for particular proteins. The affected protein is different for each SCA. The proteins in these SCAs are produced with extended repeats of glutamine amino acid in them, called polyglutamine repeat expansions, though how this causes disease is not fully understood. Dr Paola Giunti and colleagues at University College London and the National Institute of Medical Research, London are investigating how the length and nature of polyglutamine expansions affects the disease process in SCAs in an Ataxia UK-funded project; click here for details.

RESEARCH UPDATE SCA1

DISEASE MECHANISM OF SCA1

Spinocerebellar ataxia type 1 (SCA1) may begin at any age between 4 and 74 years, but most commonly becomes obvious in the fourth decade. The clinical symptoms of SCA1 are not easily distinguishable from those of other SCAs and include ataxia of gait and stance, dysarthria (problems with speech articulation) and variable degrees of paralysis of the eyes (ophthalmoplegia) (Sasaki et al 1996). However, SCA1 can be differentiated from other SCA subtypes by slowed nerve to muscle conduction time as measured by activity in the muscle following nerve stimulation (‘motor evoked potentials’) (Schöls et al 1997).

A 2004 study looking at magnetic resonance spectroscopy (MRS) brain scans of people with SCA1 and SCA2 found that there was considerable similarity between features seen in the brain with these two conditions. In SCA1 there was a correlation between the degree of abnormalities detected with the scanning measurements and the severity of the symptoms, indicating brain scans could be used to monitor progression and mark the effects of treatment trials in the future (Guerrini et al 2004).

The genetic mutation causing SCA1 was characterised by Orr et al in 1993. The mutation consists of an unstable expansion of the CAG trinucleotide repeat. In people not affected by SCA1 there may be 6-39 repeats of the CAG pattern in their DNA, whereas in SCA1 the mutated gene contains 43-81 repeats (Chong et al 1995). The length of the CAG repeat is inversely related to the age of onset; longer expansions are associated with an earlier age when symptoms first appear (Orr et al 1993). In SCA1 this abnormal polyglutamine repeat expansion occurs within a protein termed ataxin-1 (Banfi et al 1994). This protein is found in tissues throughout the body, including the nervous system. In neurones, ataxin-1 is found in the nucleus (the cell’s core, which contains most of the genetic material). In Purkinje cells of the cerebellum, which are the major site of damage in SCA1, ataxin-1 is found in the nucleus and cytoplasm (cell fluid) (Servadio et al 1995). Mutant ataxin-1 is expressed in cells throughout the body but only some cells (e.g. the Purkinje cells) appear to be damaged by this abnormal protein (Matilla-Dueñas et al 2006).

The symptoms of SCA1 are thought to be caused by the toxic effects of the expanded polyglutamine within the ataxin-1 protein, resulting in damage and death of nerve cells (Zoghbi & Orr 2000). The exact mechanisms by which the polyglutamine expansion induces cell death are not fully understood and no effective therapies are available yet.

Research using a mouse model and human material has shown that there may be many events involved in the disease mechanism of SCA1, including alterations in how other proteins are constructed (transcription) and folded into shape, effects on protein aggregation and clearance, calcium levels in cells, effects on nerve signalling (glutamate excitotoxicity) and impaired break-down of proteins (Matilla-Dueñas et al 2006).

An abnormal protein structure

Expanded polyglutamine sections in mutant proteins causes them to misfold and this might lead to difficulties in the clearance of the mutant proteins from the cell (Matilla-Dueñas et al 2006). The cell’s normal mechanism for breaking down unwanted proteins is the ubiquitin-dependent proteasome system (UPS); it relies on recognising unwanted proteins within the cell to target them for destruction. However, it may be harder for the system to recognise misfolded proteins, such as mutant ataxin-1, and this would lead to increased amounts of the mutant protein within the cell. In addition to this, polyglutamine-expanded ataxin-1 appears to compromise the function of the proteasome machinery itself (Park et al 2005). This machinery plays a major part in the removal of damaged or unwanted proteins, so failure of the system might lead to an abnormal accumulation of a variety of toxic proteins, ultimately leading to nerve cell dysfunction and/or death.

It appears that addition of phosphate (phosphorylation) to part of the ataxin-1 protein, amino acid residue serine 776, plays a crucial role in SCA1 pathogenesis (Chen et al 2003; Emamian et al 2003).

Mutant Ataxin-1 interferes with gene transcription

Increasing evidence shows that polyglutamine expanded proteins might exert abnormal effects in interaction with other proteins, disrupting their normal tasks; for example the regulation of gene expression (Matilla-Dueñas et al 2006). Ataxin-1 has been shown to interact with a number of proteins that regulate gene transcription, to bind to chromosomes and to mediate repression of transcription in cells (Lam et al 2006; Matilla et al 1997; Mizutani et al 05; Okazawa et al 2002; Serra et al, 2006; Tsai et al 2004; Tsuda et al 2005). All of these activities of ataxin-1 suggest a role in the regulation of gene transcription, and it is thought part of the disease-causing effects of mutant ataxin-1 may be caused by disruption of these events (Tsai et al 2004). Indeed, altered expression of certain genes is one of the earliest pathological changes in the primary mouse model of SCA1, occurring even before symptoms are visible; both up- and down-regulation of genes is seen (Lin et al 2000).

One of the transcriptional regulators that ataxin-1 interacts with is leucine-rich acidic nuclear protein (LANP), which mediates regulation of the transcription of specific genes in Purkinje cells (Matilla et al 1997, Cvetanovic et al 2007). In SCA1 the mutant ataxin-1’s interaction with LANP may alter its function, leading to cell loss and neurodegeneration (Matilla & Radrizzani 2005; Cvetanovic et al 2007). Studies have shown that mutant ataxin-1 can cause some genes to be up-regulated and others to be down-regulated; this could explain the mixture of gene expression changes seen in the SCA1 mouse (Cvetanovic et al 2007).

Other effects

The misfolding and subsequent aggregation of polyglutamine-expanded mutant proteins that causes neuronal dysfunction is a toxic gain of function mechanism (Matilla-Dueñas et al 2006). However in 2008, researchers suggested that a loss of the normal function of ataxin-1 itself may also contribute to the disorder. Lim et al suggested that normal ataxin-1 is involved in the formation of two different large protein complexes; a capicua-containing complex and a RBM17-containing complex. When ataxin-1 is mutated, the formation of RBM17 complex is increased; however the formation of the capicua containing complex is decreased, suggesting that there is a loss of function of that complex in SCA1 (Lim et al 2008).

Strong evidence shows that the regulation of calcium levels is disrupted in SCA1. Several of the genes in Purkinje cells that are involved in calcium homeostasis are less active in the cerebellum of SCA1 mice before any detectable symptoms of the disorder appear (Serra et al 2004; Lin et al. 2000). This suggests that disturbed calcium homeostasis in cerebellar Purkinje cells could be contributing to the damage process or affecting the survival of these cerebellar cells in SCA1 (Matilla-Dueñas et al 2006).

RESEARCH INTO POSSIBLE TREATMENTS

Genetic approaches

Research has looked at using RNA-interference (RNAi) in SCA1 mice. This is a method of ‘silencing’ genes and preventing the formation of proteins they code for. Xia et al carried out RNAi in mouse models of SCA1 and found an improvement in co-ordination, as well as more normalised cerebellar form and ataxin-1 protein aggregates (Xia et al 2004).

Ataxia UK is currently funding researchers at the Institute of Psychiatry in London as they look at addressing the phosphorylation of ataxin-1 in SCA1. Phosphorylation at amino acid residue serine 776 is required for the toxicity of mutant ataxin-1. Jean-Marc Gallo and his team are using another form of genetic modification, RNA trans-splicing, to replace the phosphorylation target residue, serine 776, with another type of amino acid, alanine, which cannot be phosphorylated. This re-programming of mutant ataxin-1 should result in reduced toxicity of the polyglutamine-expanded protein. The concept will be tested on cells grown in culture, including a cell model of SCA1. To read more about this project click here.

Other approaches

In SCA1 the ataxin-1 protein has an abnormal structure which may lead to it forming abnormal shapes. Therefore one way of fighting the disease is to prevent protein misfolding. Chaperones are molecules that aid protein folding and researchers have found that a certain chaperone molecule (HDJ-2/HSDJ) protects against ataxin-1 aggregation in a cell model of SCA1 (Cummings et al 1998). Chaperone molecules might also prevent abnormal interactions with other proteins in cell that cause toxicity (Sakahira et al 2002). Research is ongoing to study the neuroprotective potential of chaperones such as nicotinamide mononucleotide adenylyltransferase (NMNAT) in SCA1 (Zhai et al 2008).

Insulin-like growth factor-1 (IGF-1) is a protein that is found in Purkinje cells and seems to be important in maintenance and growth of nerve cells. IGF-1 levels are low in patients with late onset cerebellar ataxias and in mice models of Purkinje cell degeneration and there is evidence to suggest that IGF-1 may be protective in the cerebellar ataxias (Fernandez et al 2005). In one research study where SCA1 mice were given IGF-1 nasally every 48 hours, the treated mice showed some improvement in their performance of coordination tests (Vig et al 2006).

A study published in 2007 suggested that the psychiatric drug lithium has potential as a treatment for SCA1. Lithium can be neuroprotective in a number of other conditions and this may be due effects on gene expression. Japanese researchers tested the treatment in SCA1 mice models and found that those fed chow containing lithium showed improvements in coordination, memory and learning (Watase et al 2007).

RESEARCH INSIGHTS FROM OTHER DISEASES

We already know that the pathogenic processes of SCA is similar to that of other polyglutamine repeat disorders, e.g. Huntingdon’s disease (HD), meaning research into these other conditions may also bring benefits for people with SCA1. One possible therapeutic strategy for polyglutamine disorders is modulating the autophagic process to promote clearance of mutant proteins. Autophagy is the process by which cells digest damaged or unnecessary intracellular components or other unwanted products (e.g. bacteria). Researchers looking at mouse models of HD have found that a drug called rapamycin which acts against the molecule mTOR (a negative regulator of autophagic clearance) and various analogues of this drug can induce autophagy and reduce toxicity of polyglutamine expanded proteins (Ravikumar et al 2004). Evidence has demonstrated that autophagy plays an essential role in the clearance of ataxin-1 from the cytoplasm of cells (Iwata et al 2005).

Some work on polyglutamine expansion disorders has shown that the regulation of gene transcription is affected as a result of reduced histone acetylation. One way of restoring the balance of histone acetylation is to inhibit the histone de-acetylase (HDAC) enzymes and promising results have been seen using HDAC-inhibitors in models of polyglutamine toxicity (McCampbell et al 2001; Steffan et al 2001). HDAC-inhibiting compounds are also being looked at for treating Friedreich’s ataxia (click here for link to Friedreich’s ataxia research update) and may also be effective compounds in the treatment of spinocerebellar ataxias (Matilla-Dueñas et al 2006).

Page created March 2009

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The remainder of this page is still in preparation.

In the meantime please see here for details of current research projects on the spinocerebellar ataxias and see the latest news from international research conferences.

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