Screening for proteins with polyglutamine expansions in autosomal dominant cerebellar ataxias

Expansion of trinucleotide CAG repeats coding for polyglutamine has beenimplicated in five neurodegenerative disorders, including spinocerebellarataxia (SCA) 1 and SCA3 or Machado-Joseph disease (SCA3/MJD), two forms oftype I autosomal dominant cerebellar ataxias (ADCA). Using the 1C2 antibodywhich specifically recognizes large polyglutamine tracts, particularlythose that are expanded, we recently reported the detection of proteinswith pathological glutamine expansions in lymphoblasts from another form ofADCA type I, SCA2, as well as from patients presenting with the distinctphenotype of ADCA type II. We now have screened a large series of patientswith ADCA or isolated cases with cerebellar ataxia, for the presence ofproteins with polyglutamine expansions. A 150 kDa SCA2 protein was detectedin 16 out of 40 families with ADCA type I. This corresponds to 24% of allADCA type I families, which is much more frequent than SCA1 in this seriesof patients (13%). The signal intensity of the SCA2 protein was negativelycorrelated to age at onset, as expected for an expanded and unstabletrinucleotide repeat mutation. The disease segregated with markers closelylinked to the SCA2 locus in all identified SCA2 families. In addition, aspecific 130 kDa protein, which segregated with the disease, was detectedin lymphoblasts of patients from nine families with ADCA type II. It wasalso visualized in the cerebral cortex of one of the patients,demonstrating its translation in the nervous system. Finally, no newdisease-related proteins containing expanded polyglutamine tracts could bedetected in lymphoblasts from the remaining patients with ADCA or isolatedcases with cerebellar ataxia.