RNA-binding disturbances as a continuum from spinocerebellar ataxia type 2 to Parkinson disease

Abstract CAG triplet expansions in Ataxin-2 gene ( ATXN2 ) cause spinocerebellar ataxia type 2 and have a role that remains to be clarified in Parkinson ' s disease (PD). To study the molecular events associated with these expansions, we sequenced them and analyzed the transcriptome from blood cells of controls and three patient groups diagnosed with spinocerebellar ataxia type 2 (herein referred to as SCA2c) or PD with or without ATXN2 triplet expansions (named SCA2p). The transcriptome profiles of these 40 patients revealed three main observations: i) a specific pattern of pathways related to cellular contacts, proliferation and differentiation associated with SCA2p group, ii) similarities between the SCA2p and sporadic PD groups in genes and pathways known to be altered in PD such as Wnt, Ephrin and Leukocyte extravasation signaling iii) RNA metabolism disturbances with “RNA binding” and “poly(A) RNA binding” as a common feature in all groups. Remarkably, disturbances of ALS signaling were shared between SCA2p and sporadic PD suggesting common molecular dysfunctions in PD and ALS including CACNA1 , hnRNP , DDX and PABPC gene family perturbations. Interestingly, the transcriptome profiles of patients with parkinsonian phenotypes were prevalently associated with alterations of translation while SCA2c and PD patients presented perturbation of splicing. While ATXN2 RNA expression was not perturbed, its protein expression in immortalized lymphoblastoid cells was significantly decreased in SCA2c and SCA2p versus control groups assuming post-transcriptional biological perturbations. In conclusion, the transcriptome data do not exclude the role of ATXN2 mutated alleles in the different types of diseases but its decrease protein expression in SCA2c and also SCA2p patients suggest a potential involvement of this gene in PD. The perturbations of “RNA-binding” and “poly(A) RNA binding” molecular functions in the three patient groups as well as gene deregulations of factors not yet described in PD but known to be deleterious in other neurological conditions, suggest the existence of RNA binding disturbances as a continuum between spinocerebellar ataxia type 2 and Parkinson ' s disease.