Meredith Jackrel, University of Pennsylvania

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Event Details
  • Date/Time:
    • Tuesday November 18, 2014 - Wednesday November 19, 2014
      10:00 am - 9:59 am
  • Location: Klaus Advanced Computing Building, 2456
  • Phone:
  • URL:
  • Email:
  • Fee(s):
    N/A
  • Extras:
Contact

If you have questions about logistics or would like to set up an appointment with the speaker, please contact the School of Biology's administrative office at bio-admin@biology.gatech.edu.

Summaries

Summary Sentence: Meredith Jackrel, University of Pennsylvania

Full Summary: Potentiated Hsp104 variants antagonize diverse proteotoxic misfolding eventsThere are no therapies that reverse the proteotoxic misfolding events that underpin fatal neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS) and Parkinson’s disease (PD). Hsp104, a conserved hexameric AAA+ protein from yeast, solubilizes disordered aggregates and amyloid but has no metazoan homolog and only limited activity against human neurodegenerative disease proteins. Here, I will describe our work to reprogram Hsp104 to rescue TDP-43, FUS, and α-synuclein proteotoxicity by mutating single residues in helix 1, 2, or 3 of the middle domain or the small domain of nucleotide-binding domain 1. Potentiated Hsp104 variants enhance aggregate dissolution, restore proper protein localization, suppress proteotoxicity, and in a C. elegans PD model attenuate dopaminergic neurodegeneration. Furthermore, these potentiated variants suppress the toxicity and aggregation induced by missense mutant versions of these proteins that are associated with more severe neurodegenerative disease phenotypes. Potentiating mutations reconfigure how Hsp104 subunits collaborate, desensitize Hsp104 to inhibition, obviate any requirement for Hsp70, and enhance ATPase, translocation, and unfoldase activity. Our work establishes that disease-associated aggregates and amyloid are tractable targets and that enhanced disaggregases can restore proteostasis and mitigate neurodegeneration.

Potentiated Hsp104 variants antagonize diverse proteotoxic misfolding events

Additional Information

In Campus Calendar
No
Groups

School of Biological Sciences

Invited Audience
Undergraduate students, Faculty/Staff, Graduate students
Categories
Seminar/Lecture/Colloquium
Keywords
Meredith Jackrel, School of Biology Seminar
Status
  • Created By: Jasmine Martin
  • Workflow Status: Published
  • Created On: Nov 10, 2014 - 10:13am
  • Last Updated: Apr 13, 2017 - 5:21pm