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Presenilins : a group of novel calcium channel modulators.
Presentation on theme: "Presenilins : a group of novel calcium channel modulators."— Presentation transcript:
Presenilins: a group of novel calcium channel modulators.
Simon Kaja, Ph.D.
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
Ca2+ signaling1/3 of the genome are regulated by Ca
2+Calcium-mediated processes: -Gene transcriptionCell growth and differentiationApoptosis
resulting in moderate channel opening. Sustained Ca2+ release will result in Ca2+ occupying the low affinity, inhibitory Ca
increases channel opening, causing rapid
release. The increased rate of Ca2+ release results in an overall reduced Ca2+ release
as inhibitory concentrations
Payne et al., 2013
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
at the low affinity inhibitory
the channel and
Payne et al., 2013
Aged 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
Water maze test
Assess spatial learning and memory
Areas involved: cortical
Measures: speed, latency,
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)
Impaired spatial learning & memory with age
Kaja et al., 2013; Kaja et al.,
Impaired motor function with age
Kaja et al., 2013; Kaja et al.,
Increased in PS2 in aged cerebellumKaja et al.,
Increased PS levels in aged forebrain
Kaja et al.,
Kaja et al., in press
ConclusionsPresenilins 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
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