Abnormal dentatorubral-pallidoluysian atrophy (DRPLA) protein complex is pathologically ubiquitinated in DRPLA brains

Dentatorubral-pallidoluysian atrophy (DRPLA) is caused by expansion of a glutamine repeat in DRPLA protein. DRPLA protein undergoes greater complex formation in DRPLA brain tissue, and expanded glutamine repeat enhances complex formation of DRPLA protein. Immunoblots with and without reduction show that the DRPLA protein complex is ubiquitinated only in DRPLA brain tissue. Moreover, immunoblots of regional DRPLA brain tissues reveal that pathological ubiquitination of DRPLA protein complex is found selectively in affected lesions. Double-labeling immunohistochemical studies with antibodies against DRPLA protein and ubiquitin demonstrate that the DRPLA protein is co-localized with ubiquitin in DRPLA neurons and show characteristic neuronal cytoplasmic inclusions with ubiquitinated DRPLA protein complex in the center. Our findings suggest that DRPLA protein undergoes abnormal complex formation with expanded glutamine repeat, and then the complex is pathologically ubiquitinated in DRPLA brain tissue. Pathological ubiquitination of abnormal DRPLA protein complex plays a role in DRPLA pathology.