- The increased risk of ALS associated with longer-than-normal protein molecules caused by polyglutamine expansions appears to be a phenomenon unique to the ataxin 2 protein.
- Effects of expanded DNA sections in the ataxin 2 gene in ALS are related to a change in the function of the ataxin 2 protein.
- Although ataxin 2 repeat expansion lengths affect the risk of developing ALS, they do not correlate with age at disease onset, survival time and other specific aspects of the disease process.
In a 2010 study, scientists working in the United States and Germany found that small polyglutamine ("polyQ") expansions of DNA in the ataxin 2 gene significantly increase the risk for developing ALS (amyotrophic lateral sclerosis, or Lou Gehrig's disease).
Expansions of DNA coding for glutamine in the ataxin 2 gene lead to production of expanded ataxin 2 proteins, containing extra strings of glutamine amino acid molecules.
The number of glutamine molecules in normal ataxin 2 protein typically is 22 or 23. Expanded sections consisting of more than 34 glutamines in this protein are associated with a neurological disease called spinocerebellar ataxia 2 (SCA2).
The scientists on the 2010 study determined that "intermediate-range" expansions, consisting of 24 to 34 glutamines, are correlated with an increased risk for ALS.
Until now, however, scientists haven't been sure whether the mechanism linking longer-than-normal ataxin 2 protein molecules and increased risk of ALS is unique to the ataxin 2 protein or whether it applies to other proteins containing polyQ expansions.
Now, results from a trio of new studies not only confirm and refine scientists' understanding of the ataxin 2-associated risk for ALS; they indicate that the phenomenon, so far, appears to be unique to the ataxin 2 protein and to be related to a change in this protein's function.
Expanded ataxin 2 uniquely linked to ALS risk
The effects of glutamine expansions in ALS likely are tied to the biology, or function, of the ataxin 2 protein, not to the presence of the expansions themselves, reports a team of researchers from the University of Pennsylvania in Philadelphia, and other institutions in Philadelphia, Doylestown and Radnor, Pa.
Aaron Gitler, assistant professor of cell and developmental biology at U Penn, and colleagues, published their findings online May 11, 2011, in the journal Neurology.
Building on the 2010 study in which they identified intermediate-length glutamine expansions in ataxin 2 as a risk factor for ALS, the investigators set out to determine how the ataxin 2 expansions increase ALS risk, and whether such expansions in other genes and the proteins made from them might be associated with ALS.
The team examined the expansion lengths of seven additional genes in which expansion mutations cause dentatorubral-pallidoluysian atrophy, Huntington disease and spinocerebellar ataxia types 1, 3, 6, 7 and 17.
"Other than ataxin 2," the team reported, "we did not identify a significant association with the other polyQ genes and ALS."
Researchers noted that the effects of ataxin 2 polyQ expansions on ALS risk "are likely to be rooted in the biology of ataxin 2 or ataxin 2-specific interaction, rather than the presence of an expanded polyQ repeat, per se."
Ataxin 2 gene links ALS and spinocerebellar ataxia type 2
Particulars relevant to the ataxin 2-associated genetic overlap between ALS and the neurological disease SCA2 have been reported by Philip Van Damme at the University of Leuven in Belgium, and colleagues in Belgium and the Netherlands.
The investigators published study results, which corroborate the earlier 2010 findings, online May 11, 2011, in the journal Neurology.
In 103 people with inherited (familial) ALS, 1,845 with noninherited (sporadic) ALS and 2,002 unaffected individuals, the research team found:
- in healthy individuals, the greatest number of repeats found was 31;
- repeats numbering greater than 29 in ataxin 2 are associated with ALS;
- 32 or more repeats can underlie both sporadic and familial ALS; and
- no correlation appears to exist between repeat number and the ALS disease process.
In some cases the researchers found "clinical overlap" between ALS and SCA2, in which people with SCA2 also may show signs and symptoms of ALS.
In their report, the investigators noted that SCA2 may manifest with signs of motor neuron degeneration and that "this genetic overlap between ALS and SCA2 may contribute to our understanding of both of these neurodegenerative disorders."
PolyQ expansion lengths affect ALS risk, not disease signs and symptoms
Although polyQ expansions in ataxin 2 are linked to an increased risk of ALS, it's been found in previous studies that they don't appear to have any effect on the observable or measurable characteristics, or phenotype, in people with the disease. Now, results from a new study more clearly elucidate the lack of association between polyQ expansions and the ALS disease process.
The new findings were reported in the June 7, 2011, issue of Neurology by Elena Pegoraro, and colleagues, at the University of Padova in Padova, Italy, and at the Italian Research Center IRCCS in Venice.
The investigators examined 247 people with ALS (153 male and 94 female). The average age of onset among the study population was 57 years, with a range spanning 23 to 85 years. Nearly 75 percent of patients experienced limb onset of the disease, and the rest had bulbar-onset ALS. In three people (slightly more than 1 percent) cognitive impairment was an initial symptom of the disease.
Comparisons were made between people with ALS whose polyQ repeats within the ataxin 2 gene numbered below 24, and those with intermediate-length repeats ranging from 24 to 33.
The investigators reported no significant differences in mean age at disease onset; the ratio of limb onset to bulbar onset; average time from symptom onset to diagnosis; average FVC value (a measurement of breathing function called "forced vital capacity") at the time of initial examination; and the presence of dementia, or cognitive changes.
Within the group carrying 24 to 33 polyQ repeats, the investigators found no correlation between repeat number and age at disease onset. (The opposite is true in people with SCA2 who have an ataxin 2 polyQ repeat number greater than 33; in this population, an inverse correlation has been observed between repeat number and age at onset.)
The investigators did find that the average survival time of patients with intermediate-range repeat lengths was 35 months, versus 65 months in those whose repeats were within normal range.
The lack of any significant connection between ataxin 2 expansions in people with ALS and the way in which the disease manifests and progresses, the researchers noted, "argues against a role" for the expansions as a "clinical modifier" of ALS.
Editor's note: This story was revised on 6/29/11 to improve its clarity.