Complement and microglia mediated sensory-motor synaptic loss in Spinal Muscular Atrophy

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• George Mentis - Columbia University
• Thursday 17 May 2018, 12:00-13:00
• James Fawcett Seminar Room, van Geest Building (formerly 'the library').

If you have a question about this talk, please contact Dr Romina Vuono.

Please let Andras Lakatos (AL291@cam.ac.uk <mailto:AL291@cam.ac.uk>) know if you are interested in chatting with him after his talk, we’ll try fit you in.

Summary Spinal muscular atrophy (SMA) is a neurodegenerative disease caused by reduced levels of the ubiquitously expressed SMN protein. The hallmarks of SMA are loss of motor neurons (MN) and abnormal postural reflexes. We have shown that reduction of select synapses and sensory-motor circuit dysfunction precedes motor neuron (MN) loss. The mechanisms leading to this selective synapse loss remain unknown. Here we investigated whether complement-dependent pathways are activated and cause synapse elimination in SMA . Immunohistochemical assays in a severe mouse model of SMA , revealed that C1q, the initiating protein of the classical complement cascade, associates abnormally with excitatory synapses on MNs. We show further that both C1q and C3, a downstream complement protein, are tagging proprioceptive synapses on vulnerable MNs. Furthermore we show that synaptic elimination is mediated by phagocytic activity of reactive microglia. We finally asked, whether in vivo immunotherapy against C1q, rescues synapses destined to be eliminated and whether prevention of early synaptic loss alleviates the severe SMA phenotype. Strikingly, behavioral and morphological analysis revealed significant rescue of synapses, improved righting times, posture and lifespan. Importantly, functional assays demonstrated that synapses rescued from elimination are functional, providing further evidence that SMA is a disease of motor circuits. Collectively, our findings suggest that aberrant activation of classical complement pathway and microglial phagocytic activity mediate synaptic loss in a mouse model of SMA and identify blockade of C1q as a novel therapeutic target.

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