Distribution and pattern of pathology in subjects with familial or sporadic late-onset cerebellar ataxia as assessed by p62/sequestosome immunohistochemistry

Abstract

We investigated whether ubiquitin-binding protein p62/sequestosome-1 could be utilized to evaluate the pathology seen in patients with a clinical diagnosis of progressive late-onset cerebellar ataxia (LOCA). p62-immunoreactive (IR) lesions were assessed by means of immunohistochemistry in the brains of six LOCA cases, one with the spinocerebellar ataxia type 1 mutation (SCA1), ages at death ranging from 46 to 56 years. All cases fulfilled the criteria of olivopontocerebellar atrophy (OPCA), i.e., displaying cell loss in the predilection brain areas. One case, genetics unknown, exhibited p62-IR neuronal intranuclear inclusions (NIs). Similar NIs were labeled with the 1C2 antibody that recognizes proteins containing large polyglutamine stretches. In this case, also fused in sarcoma-IR NIs were seen. In the remaining LOCA cases, including the case with the SCA1 mutation, different kinds of nuclear and cytoplasmic p62 and 1C2 labeling but no NIs were seen. The immunoreactivity and distribution of lesions while applying p62 and 1C2 immunohistochemistry varied in our six LOCA cases fulfilling the criteria of OPCA. In all cases except in the SCA1, diffuse nuclear p62 labeling was seen, not previously reported in SCA or other neurodegenerative disorders. Due to the variability noted here as well as the limited number of cases, no assessment of progression and distributional pattern of pathology could be conducted. Based on a literature search, it is apparent that there is a need for clinico-pathologic-genetical studies of LOCA, especially to obtain a deeper understanding of the regional distribution and progression of pathology.