Simon Kaja PhD Assistant Professor Associate Director Preclinical Research University of Missouri Kansas City School of Medicine Dept of Ophthalmology Vision Research Center ID: 784663
Download The PPT/PDF document "Presenilins : a group of novel calcium ..." is the property of its rightful owner. Permission is granted to download and print the materials on this web site for personal, non-commercial use only, and to display it on your personal computer provided you do not modify the materials and that you retain all copyright notices contained in the materials. By downloading content from our website, you accept the terms of this agreement.
Slide1
Presenilins: a group of novel calcium channel modulators.
Simon Kaja, Ph.D.
Assistant
Professor, Associate Director Preclinical ResearchUniversity of Missouri – Kansas City, School of Medicine Dept. of Ophthalmology, Vision Research CenterChief Executive Officer and Co-FounderK&P Scientific LLCKansas City, MO Director North American OperationsExperimentica Ltd.Kuopio, Finalnd
Slide2Ca2+ signaling1/3 of the genome are regulated by Ca
2+Calcium-mediated processes: -Gene transcriptionCell growth and differentiationApoptosis
Synaptic plasticitySecretionNeurotransmitter releaseCell motility & contractionEnzyme activity [Ca2+] elevating pathwaysVoltage-gated Ca2+ channelsIntracellular Ca
2+ channels[Ca2+] buffering pathways
Slide3Calcium signaling in diseaseMutations in calcium channels:
MigraineAtaxiaEpilepsy Polycystic kidney diseaseHypothermia
Night-blindness Cardiac arrhythmiaTurner’s syndrome… Mutations in accessory proteins: Cerebellar ataxiaAlzheimer’s diseaseAutism
Movement disordersHypercalcemia…Age-related changes in Ca2+ signaling:Healthy agingAlzheimer’s diseaseGlaucomaDementiaParkinson’s DiseaseDry-eye disease…
Slide4Pathological cleavage of APP in AD
Slide5Presenilin proteins
Structure and function:Component of the
γ-secretaseaspartyl protease component of the γ-secretase complexTwo proteins: PS1 and PS2PS mutations linked to familial AD
PS1 and PS2 mutations increase γ-secretase activity9 TM SR/ER proteinsRationale: PS mutations increase [RyR]
Slide6Presenilin homologyPayne et al., 2013
Slide7PS1 NTF increases open probability of the brain RyR
Rybalchenko et al., 2008; and Hayrapetyan et al, 2008
Slide8PS2 NTF increases open probability of the brain RyR
Rybalchenko et al., 2008; and Hayrapetyan et al, 2008
Slide9PS NTFs differentially modulate intracellular Ca2+ release
Functional Ca
2+ imaging in SH-SY5Y
neuroblastoma cells overexpressing PS1 or PS2Payne et al., 2013
Slide10PS NTFs differentially modulate intracellular Ca2+ release
Payne et al., 2013
Slide11PS NTFs differentially modulate intracellular Ca2+ release
Payne et al., 2013
Slide12PS NTFs differentially modulate intracellular Ca2+ release
Payne et al., 2013
Slide13Model of PS modulation of the RyR
Payne et al., 2013
Ca2+ binds the high affinity stimulatory site
resulting in moderate channel opening. Sustained Ca2+ release will result in Ca2+ occupying the low affinity, inhibitory Ca
2+
binding site
resulting
in
channel closure.
Slide14PS1NTF
increases channel opening, causing rapid
Ca2+
release. The increased rate of Ca2+ release results in an overall reduced Ca2+ release
as inhibitory concentrations
are reached
faster.
Payne et al., 2013
Slide15Proposed mechanism
PS2NTF
has no effect on channel gating but blocks Ca
2+ inhibition of the RyR channel at high cytosolic Ca2+ concentrations. Significantly elevated cytosolic Ca2+ concentrations lead to eventual binding
of Ca
2+
at the low affinity inhibitory
site, closing
the channel and
resulting
in an
overall higher
cytosolic Ca
2+
concentration.
Payne et al., 2013
Slide16Aged wild-type C57/B6 mice6 months vs. 24 monthsAdvantages: Established non-genetic, inbred modelClosely mimics human condition
Many transgenic strains are based on B6 backgroundMild phenotypes compared with genetic modelsExperimental approach:Behavioral characterization
Quantification of Ca2+ signaling pathwaysCorrelation between Ca2+ signaling molecules and behavioral phenotypes
Presenilins in “healthy” aging
Slide17Behavioral paradigms
Water maze test
Assess spatial learning and memory
Areas involved: cortical
Measures: speed, latency,
pathlength
Learning Index
Bridge walking test
Assesses motor function and fine tuning
Areas involved: cerebellum
Measures: Latency to Fall (LTF); time limit: 60 sec
Latency to Fall (LTF)
Slide18Impaired spatial learning & memory with age
Kaja et al., 2013; Kaja et al.,
in press
Slide19Impaired motor function with age
Kaja et al., 2013; Kaja et al.,
in press
Slide20Increased in PS2 in aged cerebellumKaja et al.,
in press
Slide21Increased PS levels in aged forebrain
Kaja et al.,
in press
Slide22Proposed mechanism
Kaja et al., in press
Slide23ConclusionsPresenilins are potent modulators of intracellular RyR
calcium channelsThe N-terminal fragment of PS increases RyR-mediated calcium release through a direct mechanismThe ratio of PS1 to PS2 is decreased in the aging brain
Increased PS2 levels correlate with motor function deficits and cognitive declinePS2 likely contributes to AD pathogenesis when increased cytosolic calcium concentrations are present. Our data supports a role of PS proteins as part of both the calcium hypothesis and the A
β hypothesis of AD. PS proteins represent novel drug targets for neuroprotection and modulation of the intracellular calcium concentration. 9/6/2014
Slide24Acknowledgements
9/6/2014
UMKC School of MedicineVision Research Center
Peter Koulen, Ph.D. Andrew Payne, Ph.D.Bryan Gerdes, B.S.Yuliya Naumchuk, B.S.Students:Imran PuthawalaVidhi V. ShahAlexandra N. MaynardAudrey E. McCalleyCollaborators
University of Missouri – Kansas City
Nilofer Qureshi, Ph.D.
Asaf Qureshi, Ph.D.
Charles Van Way III, M.D.
Ann Smith, Ph.D.
University of
North Texas
Michael Forster, Ph.D.
Nathalie
Sumien
, Ph.D.