tailieunhanh - Báo cáo khoa học: Proteolytic processing regulates pathological accumulation in dentatorubral-pallidoluysian atrophy

Dentatorubral-pallidoluysian atrophy is caused by polyglutamine (polyQ) expansion in atrophin-1 (ATN1). Recent studies have shown that nuclear accumulation of ATN1 and cleaved fragments with expanded polyQ is the pathological process underlying neurodegeneration in dentatorubral-pallid-oluysian atrophy. | ỊFEBS Journal Proteolytic processing regulates pathological accumulation in dentatorubral-pallidoluysian atrophy Yasuyo Suzuki1 Kimiko Nakayama1 Naohiro Hashimoto2 and Ikuru Yazawa1 1 Laboratory of Research Resources Research Institute for Longevity Sciences National center for Geriatrics and Gerontology Aichi Japan 2 Department of Regenerative Medicine Research Institute for Longevity Sciences NationalCenter for Geriatrics and Gerontology Aichi Japan Keywords atrophin-1 dentatorubral-pallidoluysian atrophy DRPLA DRPLA protein neurodegeneration polyglutamine Correspondence I. Yazawa Laboratory of Research Resources Research Institute for Longevity Sciences National Center for Geriatrics and Gerontology 35 Gengo Morioka-cho Obu-shi Aichi 474-7511 Japan Fax 81 562 46 8319 Tel 81 562 46 2311 E-mail yazawa@ Received 27 July 2010 revised 9 September 2010 accepted 23 September 2010 doi Dentatorubral-pallidoluysian atrophy is caused by polyglutamine polyQ expansion in atrophin-1 ATN1 . Recent studies have shown that nuclear accumulation of ATN1 and cleaved fragments with expanded polyQ is the pathological process underlying neurodegeneration in dentatorubral-pallid-oluysian atrophy. However the mechanism underlying the proteolytic processing of ATN1 remains unclear. In the present study we examined the proteolytic processing of ATN1 aiming to understand the mechanisms of ATN1 accumulation with polyQ expansion. Using COS-7 and Neuro2a cells that express the ATN1 gene in which ATN1 was accumulated by increasing the number of polyQs we identified a novel C-terminal fragment containing a polyQ tract. The mutant C-terminal fragment with expanded polyQ selectively accumulated in the cells and this was also demonstrated in the brain tissues of patients with dentatorubral-pallidoluysian atrophy. Immunocytochemical and biochemical studies revealed that full-length ATN1 and C-terminal fragments displayed individual localization. The mutant