SCREENING FOR PROTEINS WITH POLYGLUTAMINE EXPANSIONS IN AUTOSOMAL-DOMINANT CEREBELLAR ATAXIAS

Expansion of trinucleotide CAG repeats coding for polyglutamine has be en implicated in five neurodegenerative disorders, including spinocere bellar ataxia (SCA) 1 and SCA3 or Machado-Joseph disease (SCA3/MJD), t wo forms of type I autosomal dominant cerebellar ataxias (ADCA), Using the 1C2 antibody which specifically recognizes large polyglutamine tr acts, particularly those that are expanded, we recently reported the d etection of proteins with pathological glutamine expansions in lymphob lasts from another form of ADCA type I, SCA2, as well as from patients presenting with the distinct phenotype of ADCA type II, We now have s creened a large series of patients with ADCA or isolated cases with ce rebellar ataxia, for the presence of proteins with polyglutamine expan sions, A 150 kDa SCA2 protein was detected in 16 out of 40 families wi th ADCA type I, This corresponds to 24% of all ADCA type I families, w hich is much more frequent than SCA1 in this series of patients (13%), The signal intensity of the SCA2 protein was negatively correlated to age at onset, as expected for an expanded and unstable trinucleotide repeat mutation, The disease segregated with markers closely linked to the SCA2 locus in all identified SCA2 families, In addition, a specif ic 130 kDa protein, which segregated with the disease, was detected in lymphoblasts of patients from nine families with ADCA type II, It was also visualized in the cerebral cortex of one of the patients, demons trating its translation in the nervous system, Finally, no new disease -related proteins containing expanded polyglutamine tracts could be de tected in lymphoblasts from the remaining patients with ADCA or isolat ed cases with cerebellar ataxia.