Proteostasis and aging

Question 1

what other pathways influence proteostasis aside from the core components (synthesis, folding, trafficking and degradation)

Answer 1

mitochondria, inflammation, signalling pathway eg FOXO, ILS and genetic predisposition, epigenetic, stress and environment

Question 2

what happens to the proteostasis landscape during aging

Answer 2

it deteriorates leading to decreased regulation of components

Question 3

which transcription factor mediates the heat shock response

Answer 3

HSF1

Question 4

what is the result of stress on HSF1

Answer 4

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

Question 5

how is HSF1 deactivated

Answer 5

sufficient HSP70 and 40 cause dephosphorylation or acetylation of HSF1 causing the dissociation if the trimer. HSP70 binds HSF1 monomers and sequesters it

Question 6

under what circumstances is the ER UPR activated

Answer 6

when there is overwhelming protein folding or aggregation in the `ER

Question 7

what are the 3 branches of the ER UPR

Answer 7

IRE1, AFT6 and PERK

Question 8

how does mitochondrial UPR work

Answer 8

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

Question 9

what are the 3 main stress signalling responses in eukaryotic cells to regulate proteostasis

Answer 9

heat shock response, Er UPR and Mit UPR

Question 10

why is stress signalling more complex in multicellular organisms

Answer 10

because there is non autonomous proteostasis due to cell-cell interactions as cell stress responses can be activated from one tissue t another

Question 11

how is cell stress signals transmitted between tissues in c.elegans

Answer 11

seretonin signalling factor is excreted from nerve cells to target cells of the soma which activates HSF1

Question 12

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

Answer 12

XBP-1

Question 13

how does cell-cell interaction in stress signalling promote longevity

Answer 13

improves ability to deal with stress so has a positive effect on lifespan

Question 14

how is proteostasis in weaker cells helped by cell-cell interactions

Answer 14

proteostasis effectors from a robust cell can be transported to a weaker cell

Question 15

what is the result of mutations in chaperones

Answer 15

depletion can lead to hunting tons, parkinsons and AD and specific mutations can lead to cardiovascular disease, early onset cataracts and cardiomyopathy

Question 16

what is the cause of mutations in the UPR

Answer 16

aggregation diseases including AD, tauopathies, parkinsons

Question 17

how are molecular chaperones dysregulated with going

Answer 17

they bind to aggregated proteins and are sequestered leading to less molecular chaperones in the cytosol

Question 18

how are degradation pathways dysregulated with aging

Answer 18

they’re impaired and overwhelmed so there is less import of aggregates into the proteasome

Question 19

why is proteostasis dysregulation likely to be a programmed decline

Answer 19

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

Question 20

how can signalling pathways which decline with age be stimulated in c elegan

Answer 20

stimulate neurones so they become active, leading to the production of HSP70 in the rest of the body

Question 21

how does 17-AAG activate signalling which declines with age

Answer 21

it activates HSF1 and chaperone expression