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ORIGINAL RESEARCH ARTICLE

Expression of ASC in Renal Tissues of Familial Mediterranean Fever Patients with Amyloidosis: Postulating a Role for ASC in AA Type Amyloid Deposition

Banu Balci-Peynircioglu^*,, Andrea L. Waite, Philip Schaner, Zihni Ekim Taskiran^*, Neil Richards, Diclehan Orhan, Safak Gucer, Seza Ozen^||, Deborah Gumucio and Engin Yilmaz^*,1

^* Hacettepe University, Faculty of Medicine, Department of Medical Biology, Ankara, Turkey; University of Michigan, Department of Cell and Developmental Biology, Ann Arbor, MI 48109-2200; University of Alabama at Birmingham, Division of Radiology/Oncology, Birmingham, AL 35294-3300; Hacettepe University, Faculty of Medicine, Ihsan Dogramaci Children’s Hospital, Department of Child Health, Unit of Pediatric Pathology, Ankara, Turkey; and ^|| Hacettepe University, Faculty of Medicine, Ihsan Dogramaci Children’s Hospital, Department of Child Health, Nephrology and Rheumatology Unit, Ankara, Turkey

To whom requests for reprints should be addressed at ¹ Hacettepe University, Tip Fakultesi, Tibbi Biyoloji AD, Rektorluk Binasi, A Kapisi, 4. Kat, 06100 Sihhiye, Ankara, Turkey. E-mail: eyilmaz{at}hacettepe.edu.tr

Familial Mediterranean fever (FMF) is characterized by recurrent attacks of fever and serositis; in some cases, ensuing amyloidosis results in kidney damage. Treatment with colchicine reduces the frequency and severity of FMF attacks and prevents amyloidosis, although the mechanisms behind these effects are unknown. Pyrin, the protein product of the MEFV gene, interacts with ASC, a key molecule in apoptotic and inflammatory processes. ASC forms intracellular speck-like aggregates that presage cell death. Here we show that cell death after ASC speck formation is much slower in nonmyeloid cells than in myeloid cells. Additionally, we demonstrate that colchicine prevents speck formation and show that specks can survive in the extracellular space after cell death. Because we also found that ASC is expressed in renal glomeruli of patients with FMF but not in those of control patients, we posit that high local ASC expression may result in speck formation and that specks from dying cells may persist in the extracellular space where they have the potential (perhaps in association with pyrin) to nucleate amyloid. The fact that speck formation requires an intact microtubule network as shown here could potentially account for the ability of prophylactic colchicine to prevent or reverse amyloidosis in patients with FMF.

Key Words: ASC • amyloidosis • speck • microtubules