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SUMMARY:An all optical approach to study amyloid aggregation - Doctor Gabr
 iele Kaminski Schierle
DTSTART:20180321T110000Z
DTEND:20180321T120000Z
UID:TALK103066@talks.cam.ac.uk
CONTACT:Kirsty Shepherd
DESCRIPTION:Understanding the formation and structural characteristics of 
 amyloid fibrils is vital for the development of therapeutics for many neur
 odegenerative disorders. We have developed a fluorescence-lifetime based a
 ggregation sensor that can readily be applied in vitro and in vivo\, permi
 tting the screening of small molecule drugs against protein aggregation. I
 n order to characterise amyloid fibril growth\, we apply two colour total 
 internal reflection microscopy and super-resolution imaging and demonstrat
 e that there is heterogeneity in the growth rates of individual amyloid fi
 brils which can be attributed to structural polymorphism. \nIn order to un
 derstand the normal physiological and pathological function of alpha-synuc
 lein\, a protein linked to Parkinson’s disease\, we have applied a combi
 nation of optical NMR\, and mass spectroscopy techniques. We have discover
 ed that alpha-synuclein acts as a calcium sensor at the pre-synapse. In pa
 rticular\, we show that a sub-group of alpha-synuclein-positive vesicles a
 t the pre-synapse is specifically responsive to changes in calcium concent
 rations. This is in contrast to VAMP-2 positive vesicles that do not form 
 localised clusters at the pre-synapse upon calcium exposure. NMR and mass 
 spec data indicate that this calcium sensing capacity of alpha-synuclein i
 s mediated via the negatively charged C-terminus\, which\, upon calcium bi
 nding\, directly interacts with synaptic vesicles. We further demonstrate 
 that the alpha-synuclein calcium sensor needs to be finely tuned as increa
 sed levels of calcium over a prolonged time in the presence of alpha-synuc
 lein can directly result in pathology. Similarly\, using a cell model of P
 arkinson’s disease\, toxicity can be prevented either by a decrease in t
 he level of alpha-synuclein or by isradipine\, a voltage-gated calcium cha
 nnel inhibitor.\nIn summary\, by applying primarily optical techniques we 
 have shed light on amyloid protein function\, aggregation kinetics and str
 uctural characteristics that together may help to develop therapeutic stra
 tegies against various forms of neurodegenerative diseases.\n
LOCATION:Centre for Advanced Photonics and Electronics\, 9\, JJ Thompson A
 ve.
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