Expanded ataxin-2 polyQ repeats have been shown to result in a cerebellar ataxia phenotype (SCA2) (4
). It was recently proposed that expanded repeat expansions of the ATXN2
repeat increase the risk of ALS (13
). Herein, we have shown that the risk observed for ATXN2
repeats is not limited to ALS, but is also observed in another neurodegenerative disease, PSP, a four-repeat (4R) tauopathy. The strongest association was observed with expanded ATXN2
repeats lengths >30 units in ALS (OR = 5.57, P
= 0.001) and PSP (OR = 5.83, P
= 0.004), in accordance with a recent follow-up study performed in European ALS patients which suggested that longer ATXN2
repeats resulted in a more clear association with disease (15
No significant association was demonstrated for the other neurodegenerative disorders examined in the present study: AD, PD and FTLD; although a number of expanded repeat carriers were observed in these disease groups. In the case of AD and PD, the lack of association may suggest that the aggregation of the major proteins underlying these disorders (amyloid-β and α-synuclein) is not influenced by an expanded polyQ repeat in ataxin-2. However, for FTLD, where the majority of patients are found to have either TDP-43 or tau pathology at autopsy, we also did not observe an association. Given the clinical and pathological heterogeneity in these disorders, even larger sample series and meta-analytical approaches may be required to fully resolve the role of ATXN2 repeats in other neurodegenerative disorders.
Importantly, in contrast to previous reports, we did identify 9 of 4877 (0.2%) healthy control carriers with repeat lengths >30 units. The presence of ataxin-2 polyQ repeat length expansions within our controls series may reflect an age-related reduced disease penetrance. In fact, several of these controls are currently below the average onset age observed in our patient cohorts and may develop disease at an older age. Conversely, the sporadic nature of these late-onset neurodegenerative disorders suggests that many other factors in addition to ATXN2 repeat length may contribute to the disease penetrance and phenotypic presentation. Together our findings demonstrate the importance of large control series and promote caution in the designation of pathogenicity due to an expanded repeat in ATXN2 for phenotypes other than SCA2.
The most frequent ATXN2
repeat length appears to be a 22 repeat consisting of the (CAG)8
trinucleotide sequence (16
). It has been observed that SCA2 patients with expansions (>31 units) have a pure CAG repeat and do not harbor the CAA interruptions (2
). Although the CAA codons do not alter the amino acid residue, they can result in branched structures at the DNA and RNA level in vitro
). Interestingly, it has been postulated that expanded repeats that contain the CAA codons can produce a more heterogeneous clinical phenotype resembling a myriad of parkinsonian and neurodegenerative disorders, including PD, PSP, MSA and most recently ALS (7
). In fact, in a recent study, expanded repeat alleles of 40 ALS patients and 9 controls were sequenced and all repeats were found to be interrupted (18
). Cloning and sequencing of the expanded repeat alleles in a selection of our patients diagnosed with ALS, FTLD, AD, PSP and PD also showed CAA interruptions. More detailed analysis of the internal repeat structure further demonstrated that expansions had occurred via at least two mechanisms resulting in different internal repeat structures in our carriers. Although we only analyzed a limited number of patients, our findings suggested that there may be no correlation between the internal repeat structure and specific clinical or pathologic phenotypes.
As previously shown by Elden et al
), expanded ataxin-2 polyQ repeats enhance the interaction of ataxin-2 with TDP-43 and promote TDP-43 mislocalization under situations of stress, which could explain the increased risk for ALS. However, PSP is a 4R-tauopathy and most patients are not found to have TDP-43 pathology at autopsy. Our PSP patient with the longest ATXN2
repeat was negative for TDP-43 immunostaining (data not shown). Therefore, it will be critically important to determine whether expanded ataxin-2 polyQ repeats could also promote protein aggregation or mislocalization of other neurodegenerative disease associated proteins, including tau.
Future studies are now needed to elucidate the underlying pathomechanism involving ataxin-2 polyQ repeat length expansions. Given the alternate pathologies associated with ATXN2 repeats observed in our study, we suggest that the ataxin-2 protein may play a role in neurodegenerative diseases other than ALS.