Proteostasis and aging Flashcards
what other pathways influence proteostasis aside from the core components (synthesis, folding, trafficking and degradation)
mitochondria, inflammation, signalling pathway eg FOXO, ILS and genetic predisposition, epigenetic, stress and environment
what happens to the proteostasis landscape during aging
it deteriorates leading to decreased regulation of components
which transcription factor mediates the heat shock response
HSF1
what is the result of stress on HSF1
monomers trimerise and undergo translational modifications including phosphorylation. it then translocates to the nucleus and binds gene promoter sequences containing TTCGAATTC which activates heat shock elements producing chaperones such as HSP70,90 and 40
how is HSF1 deactivated
sufficient HSP70 and 40 cause dephosphorylation or acetylation of HSF1 causing the dissociation if the trimer. HSP70 binds HSF1 monomers and sequesters it
under what circumstances is the ER UPR activated
when there is overwhelming protein folding or aggregation in the `ER
what are the 3 branches of the ER UPR
IRE1, AFT6 and PERK
how does mitochondrial UPR work
under stress conditions CLpP protease cleaves misfolded proteins. Peptides are transported out of the mitochondria by HAF-1 which activates ATFS1, a transcription factor. ATFS1 translocates into the nucleus along with DVE1 and UBL5 inducing transcription of mitochondrial specific chaperones
what are the 3 main stress signalling responses in eukaryotic cells to regulate proteostasis
heat shock response, Er UPR and Mit UPR
why is stress signalling more complex in multicellular organisms
because there is non autonomous proteostasis due to cell-cell interactions as cell stress responses can be activated from one tissue t another
how is cell stress signals transmitted between tissues in c.elegans
seretonin signalling factor is excreted from nerve cells to target cells of the soma which activates HSF1
which transcription factor activated in neurones as a result of ER UPR leads to up regulation of ER specific chaperones in rest of the body
XBP-1
how does cell-cell interaction in stress signalling promote longevity
improves ability to deal with stress so has a positive effect on lifespan
how is proteostasis in weaker cells helped by cell-cell interactions
proteostasis effectors from a robust cell can be transported to a weaker cell
what is the result of mutations in chaperones
depletion can lead to hunting tons, parkinsons and AD and specific mutations can lead to cardiovascular disease, early onset cataracts and cardiomyopathy
what is the cause of mutations in the UPR
aggregation diseases including AD, tauopathies, parkinsons
how are molecular chaperones dysregulated with going
they bind to aggregated proteins and are sequestered leading to less molecular chaperones in the cytosol
how are degradation pathways dysregulated with aging
they’re impaired and overwhelmed so there is less import of aggregates into the proteasome
why is proteostasis dysregulation likely to be a programmed decline
because in c. elegant components collapse early into adulthood and myosin fibres start to disintegrate and aggregat after 3 days of adulthood and after 4 hours induction of heat shock response more than halves leading to reduced stress resistance. this is a result of epigenetic changes as deacetylation prevents transcription factors binding DNA promoter
how can signalling pathways which decline with age be stimulated in c elegan
stimulate neurones so they become active, leading to the production of HSP70 in the rest of the body
how does 17-AAG activate signalling which declines with age
it activates HSF1 and chaperone expression
