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CATEGORIES:rv254's list
SUMMARY:Complement and microglia mediated sensory-motor sy
 naptic loss in Spinal Muscular Atrophy - George Me
 ntis - Columbia University
DTSTART;TZID=Europe/London:20180517T120000
DTEND;TZID=Europe/London:20180517T130000
UID:TALK96910AThttp://talks.cam.ac.uk
URL:http://talks.cam.ac.uk/talk/index/96910
DESCRIPTION:Summary\nSpinal muscular atrophy (SMA) is a neurod
 egenerative disease caused by reduced levels of th
 e ubiquitously expressed SMN protein. The hallmark
 s of SMA are loss of motor neurons (MN) and abnorm
 al postural reflexes. We have shown that reduction
  of select synapses and sensory-motor circuit dysf
 unction precedes motor neuron (MN) loss. The mecha
 nisms leading to this selective synapse loss remai
 n unknown. Here we investigated whether complement
 -dependent pathways are activated and cause synaps
 e elimination in SMA. Immunohistochemical assays i
 n a\nsevere mouse model of SMA\, revealed that C1q
 \, the initiating protein of the classical complem
 ent cascade\, associates abnormally with excitator
 y synapses on MNs. We show further that both C1q a
 nd C3\, a downstream complement protein\, are tagg
 ing proprioceptive synapses on vulnerable MNs. Fur
 thermore we show that synaptic elimination is medi
 ated by phagocytic activity of reactive microglia.
 \nWe finally asked\, whether in vivo immunotherapy
  against C1q\, rescues synapses destined to be eli
 minated and whether prevention of early synaptic l
 oss alleviates the severe SMA phenotype. Strikingl
 y\, behavioral and morphological analysis revealed
  significant rescue of synapses\, improved rightin
 g times\, posture and lifespan. Importantly\, func
 tional assays demonstrated that synapses rescued f
 rom 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 mi
 croglial phagocytic activity mediate synaptic loss
  in a mouse model of SMA and identify blockade of 
 C1q as a\nnovel therapeutic target.
LOCATION:James Fawcett Seminar Room\, van Geest Building (f
 ormerly 'the library')
CONTACT:Dr Romina Vuono
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