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SUMMARY:Complement and microglia mediated sensory-motor synaptic loss in S
 pinal Muscular Atrophy - George Mentis - Columbia University
DTSTART:20180517T110000Z
DTEND:20180517T120000Z
UID:TALK96910@talks.cam.ac.uk
CONTACT:Dr Romina Vuono
DESCRIPTION:Summary\nSpinal 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 postura
 l reflexes. We have shown that reduction of select synapses and sensory-mo
 tor circuit dysfunction precedes motor neuron (MN) loss. The mechanisms le
 ading to this selective synapse loss remain unknown. Here we investigated 
 whether complement-dependent pathways are activated and cause synapse elim
 ination in SMA. Immunohistochemical assays in a\nsevere mouse model of SMA
 \, revealed that C1q\, the initiating protein of the classical complement 
 cascade\, associates abnormally with excitatory synapses on MNs. We show f
 urther that both C1q and C3\, a downstream complement protein\, are taggin
 g proprioceptive synapses on vulnerable MNs. Furthermore we show that syna
 ptic elimination is mediated by phagocytic activity of reactive microglia.
 \nWe finally asked\, whether in vivo immunotherapy against C1q\, rescues s
 ynapses destined to be eliminated and whether prevention of early synaptic
  loss alleviates the severe SMA phenotype. Strikingly\, behavioral and mor
 phological analysis revealed significant rescue of synapses\, improved rig
 hting times\, posture and lifespan. Importantly\, functional assays demons
 trated that synapses rescued from elimination are functional\, providing f
 urther evidence that SMA is a disease of motor circuits. Collectively\, ou
 r findings suggest that aberrant activation of classical complement pathwa
 y and microglial phagocytic activity mediate synaptic loss in a mouse mode
 l of SMA and identify blockade of C1q as a\nnovel therapeutic target.
LOCATION:James Fawcett Seminar Room\, van Geest Building (formerly 'the li
 brary')
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