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First Class Lecture notes Dynamic Cell Module
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- Dynamic Cell Module
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- University Of Bath (UoB)
Proteostasis lecture notes
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JL: OVERVIEW OF PROTEOSTASISDefine Proteostasis
Proteostasis refers to a balance of proteins within cells, the life cycle of proteins. Protein
synthesis must be balanced with protein turnover/degradation. If this fine balance is not
regulated, diseases such as PD occur.
Study of cell biology:
-- Visual observation have been key to our understanding (from basic microscopy, to now
crystallography, NMR, cryo-EM)
-- Robert Hooke observes cells
of a cork tree trough a
primitive microscope
-- Antonie van Leewenhoek is
considered the first
microbiologist. He observed
the first Protozoa (unicellular
eukaryotic organisms with
animal like properties in terms
of predation and migration)
and microbe. The first to
document microscopic
observation of muscle fibers,
bacteria, spermatozoa.
-- Nägeli was one of the first
to differentiate the plant cell
wall from the cytoplasm and nucleus, which in 1846 German botanist Hugo von Mohl
called protoplasm.
-- Aged 25 he wrote a paper on pollen formation of seed and flowering plants and
described cell division with great accuracy. He noted what he called transitory cytoblasts,
which later were identified as chromosomes. He also witnessed cell division and
investigated the process of osmosis in unicellular algae.
-- Golgi used a “black reaction” where silver nitrate react with potassium dichromate. This
results in black deposit on the soma of neurons, and also on the axon ad dendrites,
showing a well-contrasted picture on a yellow background.
The study of the cell dates back to 17 th century with discovery of the unit of the cell. Most
discoveries over the last century enabled by technologies such as microscopy and staining etc.
Content of lectures discovered recently, in last 20-30 years e.g. Autophagy, lysosome, UPS. Ageing is
linked to protein homeostasis – C.elegans has advantage of 18 day life cycle, used to study ageing.
Strong evidence that ageing mechanisms highly depend on how well protein levels are balanced
within cells.
Discuss a key signaling pathway involved in
aging and how it affect proteostasis.
Why and how do we age? -- Why do different organisms have different lifespans?
, C.elegans (Caenorhabditis elegans): model of choice to study longevity:-
-- Up until the 1960s aging was thought to be a random process of cellular deterioration that
occurred independently of genetic control.
-- Mutation screen of C.elegans identified DAF2 (IGF1 in mammals) as a longevity associated
genes.
-- If DAF2 is not functional (mutated gene) then worms live longer and appear healthier than
wild type (wt) controls.
Insulin/IGF1 signalling pathways regulate cell ageing:
-- Discovery made that these genes
regulating longevity in C.elegans were also
present in other organisms e.g. Drosophila,
mammals - conserved signalling cascades.
Signalling cascade involves regulation of
metabolic genes involved in protein
homeostasis. Signalling cascades are also
regulated by environment – environment
worm lives in e.g stress, food availability
influences protein homeostasis.
-- Extra: It has been demonstrated in
invertebrate species that the evolutionarily
conserved insulin and insulin-like growth
factor (IGF) signaling (IIS) pathway plays a major role in the control of longevity. In the
roundworm Caenorhabditis elegans, single mutations that diminish insulin/IGF-1 signaling
can increase lifespan more than twofold and cause the animal to remain active and youthful
much longer than normal. Likewise, substantial increases in lifespan are associated with
mutations that reduce insulin/IGF-1 signaling in the fruit fly Drosophila melanogaster. In
invertebrates, multiple insulin-like ligands exist that bind to a common single insulin/IGF-1
like receptor. In contrast, in mammals, different receptors exist that bind insulin, IGF-1 and
IGF-2 with different affinities. In several mouse models, mutations that are associated with
decreased GH/IGF-1 signaling or decreased insulin signaling have been associated with
enhanced lifespan.
How do signalling pathways regulate cell ageing?
-- Key signaling pathways including IGF1 impact on longevity and youthfulness
through the regulation of proteostasis .
-- Proteostasis is the process that regulates protein within cells. Proteostasis
involves a highly complex interconnection of pathways that influence protein
fate from their synthesis to their degradation
-- Figure legend from Douglas and Dillin 2010: Environmental cues such as
food availability or extrinsic stress alter age-modifying, signaling pathways
such as insulin/IGF-1, target of rapamycin (TOR), sirtuins, heat shock factor
(HSF), and hypoxia-inducible factor (HIF-1). Elaborate interplay between the
different signaling pathways modulates proteostasis and impacts onset and
progression of numerous neurodegenerative diseases.
Proteostasis landscape deteriorates with time:
-- Proteostasis declines as a function of time and may provide a plausible explanation as to
why age is a major risk factor for such neurodegenerative diseases.
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