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Investigating the roles of the Hsp90 co-chaperone, STI1, in neuronal resilience during aging

Presented at: Neuroscience 2020
C.E. Credits: P.A.C.E. CE Florida CE
Speaker
  • PhD Candidate in Neuroscience, Robarts Research Institute, The University of Western Ontario
    Biography
      Rachel Lackie is a senior PhD Candidate in the Neuroscience program at the University of Western Ontario (UWO). Rachel Lackie's research interests during her PhD have been to investigate the roles of a neuroprotective co-chaperone protein in normal aging, and in Alzheimer's and Parkinson's disease mouse models. Specifically, her research has focused on how this protein regulates protein misfolding and aggregation, as well as neuronal survival. Rachel Lackie has been successful in acquiring competitive external scholarships for the past four years to fund her research, including Ontario Graduate Scholarships and an Alzheimer's Society Research Program Doctoral Scholarship. Rachel Lackie has published 3 peer reviewed manuscripts, including a review paper that was published in 2017 and has been cited over 90 times. Outside of the lab, Rachel Lackie participates in two Science Outreach initiatives. Firstly, she is a Recruitment Coordinator for the Retiring with Strong Minds subcommittee of Strong Bones, Strong Minds, Strong Muscles a UWO graduate student run program that brings graduate students to present their research at retirement residences across London, to allow engagement between researchers and the general public. Secondly, Rachel Lackie is a Reviewing Editor for a neuroscience blog called the Dorsal Column, which highlights published research from UWO, with news articles being written by current Neuroscience graduate students. The blog is geared towards the non-scientific community to let the public know about novel and exciting Neuroscience research occurring at UWO.

    Abstract

    Chaperone networks are dysregulated with aging, but whether compromised Hsp70/Hsp90 chaperone function disturbs neuronal resilience is unknown. Stress‐inducible phosphoprotein 1 (STI1; STIP1; HOP) is a co‐chaperone that simultaneously interacts with Hsp70 and Hsp90, but whose function in vivo remains poorly understood. We combined in‐depth analysis of chaperone genes in human datasets, analysis of a neuronal cell line lacking STI1 and of a mouse line with a hypomorphic Stip1 allele to investigate the requirement for STI1 in aging. Our experiments revealed that dysfunctional STI1 activity compromised Hsp70/Hsp90 chaperone network and neuronal resilience. The levels of a set of Hsp90 co‐chaperones and client proteins were selectively affected by reduced levels of STI1, suggesting that their stability depends on functional Hsp70/Hsp90 machinery. Analysis of human databases revealed a subset of co‐chaperones, including STI1, whose loss of function is incompatible with life in mammals, albeit they are not essential in yeast. Importantly, mice expressing a hypomorphic STI1 allele presented spontaneous age‐dependent hippocampal neurodegeneration and reduced hippocampal volume, with consequent spatial memory deficit. We suggest that impaired STI1 function compromises Hsp70/Hsp90 chaperone activity in mammals and can by itself cause age‐dependent hippocampal neurodegeneration in mice.

    Learning Objectives:

    1. Introduce the advantages of using a hypomorphic allele mouse model to study the chaperone machinery in mice.

    2. Learn about a protein that is a potential key player in neurodegeneration and aging.


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