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Dissecting neuronal regulatory pathways of the cellular heat shock response to elevated temperatures and misfolded proteins

Applicant Dr. Carmen Krammer
Subject Area Cell Biology
Term from 2009 to 2011
Project identifier Deutsche Forschungsgemeinschaft (DFG) - Project number 120237058
 
Final Report Year 2011

Final Report Abstract

Proteinopathies are
 characterized
 by
 the
chronic
 expression
 of
 misfolded 
proteins.
 The
 aggregation
 process
 was
 anticipated
 to
 take
 place
 strictly
 cell
 autonomously
 and
 unaffected
 by
 the
 cellular
 environment.
 Accumulating
 evidence
 now
 suggests,
 that
 cell‐to‐cell
 transmission
 of
 protein
 aggregates
 might
 occur
 in
 several
 neurodegenerative
 disorders
 and
 contribute
 to
 disease
 pathology.
 To
 test
 whether
 cytosolic
 protein
 aggregates
 can
 spread
 in
 a
 multicellular
 organism
 we
 used
 the
 yeast
 prion
 protein
 Sup35p,
 a
 cytosolic
 protein
 that
 is
 able
 to
 propagate
 its
 aggregated
 conformation
 in
 yeast
 and
 in
 mammalian
 cell
 culture.
 We
 generated
 transgenic
 Caenorhabditis
 elegans
 lines
 expressing
 the
 prion
 domain
 (NM)
 of
 Sup35p,
as well
as
 Sup35NM 
bearing 
a
 deletion 
in 
the
 oligorepeat 
region
(RΔ2‐5)
 or
 an
 extended
 oligorepeat
 region
 (R2E2).
 Similarly
 as
 in
 yeast,
 these
 proteins
 aggregate
 in
 an
 oligorepeat
 region
 length
 dependent
 manner:
 R2E2
 is
 highly
 aggregation‐prone,
 whereas
 RΔ2‐5
 remains
 mostly
 soluble.
 Upon
 co‐expression
 in
 the 
same
 cells,
R2E2
 promotes 
the 
aggregation 
of
 RΔ2‐5,
despite 
a
 very 
low
 or
 only
 transient
co‐localization.
 Although
 expressed 
under
 a
 muscle
 cell
 specific
 promoter,
 R2E2
 was
 detected
 in
 coelomocytes,
 phagocytes
 residing
 in
 the
 body
 cavity,
 indicating 
that
 R2E2 
is
 being 
released 
from
 muscle
cells.
 Remarkably,
 R2E2
 was
 able
 to
 induce
 RΔ2‐5
 aggregation
 expressed
 in
 another
 tissue.
 Thus,
 in
 a
 multicellular
 organism,
 compromised
 cells
 are
 able
 to
 affect
 global
 proteostasis
 in
 a
 non‐cell
 autonomous
 manner.


Publications

  • Prion‐like
 propagation 
of
 cytosolic 
protein
 aggregates:
 insights 
from 
cell 
culture 
models.
 Prion.
 Oct.
 2009
    Krammer
 C, 
Schaetzl 
HM,
 Vorberg
 I
 
 

Additional Information

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