Abstract
Recent evidence of prion-like propagation of α-synuclein (α-syn) into neighboring neurons set up a paradigm to elucidate the mechanism of progression of Parkinson's disease (PD) and to develop therapeutic strategies. Here, we show that FcγRIIB expressed in neurons functions as a receptor for α-syn fibrils and mediates cell-to-cell transmission of α-syn. SHP-1 and 2 are activated downstream by α-syn fibrils through FcγRIIB and play an important role in cell-to-cell transmission of α-syn. Also, taking advantage of a co-culture system, we show that cell-to-cell transmission of α-syn induces intracellular Lewy body-like inclusion body formation and that the FcγRIIB/SHP-1/2 signaling pathway is involved init. Therefore, the FcγRIIB-SHP-1/-2 signaling pathway may be a therapeutic target for the progression of PD. The invitro system is an efficient tool for further high-throughput screening that can be used for developing a therapeutic intervention in PD.
Highlights
Parkinson’s disease (PD) is a common progressive neurodegenerative disorder characterized pathologically by loss of dopaminergic neurons located in the midbrain and the presence of intraneuronal inclusions, called Lewy bodies or Lewy neurites, consisting mainly of aggregates of a-synuclein (a-syn)
These results suggest that transferred a-syn fibrils induce FcgRIIB/SHP-1/2 signaling to mediate transferred a-syn-induced Lewy body-like inclusion body formation
We demonstrated that FcgRIIB expressed in neurons functions as a receptor for a-syn fibrils and mediates cell-to-cell transmission of a-syn. a-Syn fibrils bound to FcgRIIB in neurons, and downregulation of FcgRIIB suppressed cell-to-cell transmission of a-syn, further inhibiting Lewy body-like inclusion body formation induced by transferred a-syn
Summary
Prion-like propagation of a-synuclein (a-syn) may contribute to the progression of Parkinson’s disease. Choi et al demonstrate that FcgRIIB functions as a receptor for a-syn fibrils and that the FcgRIIB-SHP-1/2 signaling pathway mediates cell-to-cell transmission of a-syn. Blocking this signaling pathway attenuates transmission, suppressing Lewy body-like inclusion body formation. Highlights d a-Syn fibrils bind to FcgRIIB expressed in neurons d FcgRIIB mediates cell-to-cell transmission of a-syn as a receptor, transmitting signals to enhance it d SHP-1/2 activation by FcgRIIB is essential for cell-to-cell transmission of a-syn d Blocking this signaling pathway attenuates Lewy body-like inclusion body formation. 2018, Cell Reports 22, 136–148 January 2, 2018 a 2017 The Author(s).
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