AGG Repeat Expansion and Aggregation of BIN1 in Multiple System Atrophy
Kume, K.; Kurashige, T.; Itabashi, T.; Akagi, A.; Ando, T.; Nakamura, M.; Kikumoto, M.; Tamada, A.; Kamada, M.; Ayaki, T.; Izumi, Y.; Yabe, I.; Muguruma, K.; Miyamoto, T.; Iwasaki, Y.; Kawakami, H.
Show abstract
Multiple system atrophy (MSA) is a fatal, sporadic -synucleinopathy characterized by glial cytoplasmic inclusions (GCIs) in oligodendrocytes. No causative gene for MSA has been identified to date. Herein, we report an intronic AGG repeat expansion in BIN1, a major susceptibility gene for Alzheimers disease, in a familial MSA case and 13% of autopsy-confirmed sporadic cases. In one case, the expansion was detected only in the cerebellum, implicating somatic mosaicism in disease pathogenesis. The BIN1 protein aggregate localized to GCIs and associated with -synuclein fibrils. Notably, BIN1 was absent from Lewy bodies, highlighting a potential MSA-specific role. Our findings indicate a novel somatically unstable repeat expansion contributing to MSA and support the notion that BIN1 aggregation plays a central role in disease-specific protein pathology. One-Sentence SummaryRepeat expansion and accumulation of BIN1 play an important role in the pathogenesis of multiple system atrophy.
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