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Spatial protein quality control and its links to aging, proteotoxicity, and polarity

Objective

Propagation of a species requires periodic cell renewal to avoid clonal senescence. My
laboratory has described a new mechanism for such cell renewal in yeast, in which damaged
protein aggregates are transported out of the daughter buds along actin cables to preserve
youthfulness. Such spatial protein quality control (SQC) is a Sir2p-dependent process and by establishing the global genetic interaction network of SIR2, we identified the
polarisome as the machinery required for mitotic segregation and translocation of protein
aggregates. In addition, we found that the fusion of smaller aggregates into large inclusion
bodies, a process that has been suggested to reduce the toxicity of such aggregates, requires
actin cables and their nucleation at the septin ring. Sir2p controls damage segregation by
affecting deacetylation and the activity of the chaperonin CCT, enhancing actin folding and
polymerization. Considering that CCT has been implicated in mitigating
aggregation/toxicity of polyglutamine proteins, e.g. huntingtin, and that actin cables is
affecting formation, fusion, and resolution of aggregates, we hypothesize that CCT
deacetylation may underlie Sirt1¿s (mammalian orthologues of Sir2p) documented beneficial
effects in several neurodegenerative disorders caused by proteotoxic aggregates. This project
is aimed at approaching this hypothesis and to elucidate, on a genome-wide scale, how the
cell tether, sort, fuse, and detoxify aggregates with the help of CCT, actin cables, and the
polarity machinery. This will be accomplished by combining the power of synthetic genetic
array analysis, high-content imaging, genome wide proximity ligand assays, and microfluidics.
Using such approaches, the project seeks to decipher the machineries of the spatial quality
control network as a means to identify new therapeutic targets that may retard or postpone
the development of age-related maladies, including neurodegenerative disorders.
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Principal Investigator

Lars Bertil Thomas Nyström (Prof.)

Host institution

GOETEBORGS UNIVERSITET

Address

Vasaparken
405 30 Goeteborg

Sweden

Activity type

Higher or Secondary Education Establishments

EU Contribution

€ 2 371 262

Principal Investigator

Lars Bertil Thomas Nyström (Prof.)

Administrative Contact

Ludde Edgren (Dr.)

Beneficiaries (1)

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GOETEBORGS UNIVERSITET

Sweden

EU Contribution

€ 2 371 262

Project information

Grant agreement ID: 268630

Status

Closed project

  • Start date

    1 June 2011

  • End date

    31 May 2016

Funded under:

FP7-IDEAS-ERC

  • Overall budget:

    € 2 371 262

  • EU contribution

    € 2 371 262

Hosted by:

GOETEBORGS UNIVERSITET

Sweden