Pathological Spreading of Disease Flashcards
Propagation is the _______________ of protein aggregates from one cell to another followed by _____________ of aggregation int eh receiving cell.
transmission; seeding
What are the requirements for transmission?
- RELEASE from cell
- compartment/entry point BIG ENOUGH to allow for transport of the seed
- uptake by a CONNECTED CELL (major factor is distance)
- delivery into a SUITABLE COMPARTMENT in recipient cells
What are the requirements for seeding?
- seed in CORRECT compartment
- AVAILABLE MONOMER for formation of new aggregates
- STABLE SEED that can maintain shape and not be degraded
What are the factors affecting spreading of variant aggregates?
- ability to seed
- ability to be transmitted
- ability to avoid degradation
What aspect of the aggregate may be key to which pathology develops?
shape
TRUE or FALSE: the same protein will lead to the same NDD, even if the shape is different
FALSE: different shapes can lead to distinct NDD
What was the difference in seeding observed in the experiment where tau aggregates were injected into mice hippocampus? Which seeds produced glial pathology?
- AD and CBD = low seeding
- PSP = high seeding (more positive staining)
- CBD and PSP seeds –> glial pathology
TRUE or FALSE: in the experiment where tau aggregates were injected into mice hippocampus, each seed produced pathology in DISTINCT brain regions and patterns, despite injection into the SAME brain area
TRUE
What are the prion diseases in humans, sheep, and cows?
- humans = KURU by ingesting infected human brain
- sheep = SCRAPIE by ingesting infected feed or env contamination
- cow = MAD COW DISEASE by ingesting contaminated feed
How is it possible that ingesting prions can lead to a NDD?
- prions can survive acidic environment of the gut
- cross epithelial layer
- interact with immune cells
- bind FDC
- transmit to nerve fibers (due to proximity)
What harsh conditions does PrPsc need to survive the gut environment and passage through cells?
- acidic pH of gut, which normally denatures most proteins
- proteases function to break down proteins we ingest
Why might FDCs be efficient at PrPsc propagation?
they express sufficient levels of PrPc
What are the first neurons that allow PrPSc into the nervous system?
neurons of the ENTERIC nervous system
TRUE or FALSE: PrPc is more stable than PrPSc
FALSE: PrPSc fibrils are more stable than its expressed monomer form, PrPc
___________ might trigger alpha-synuclein pathology
inflammation
PD patients report ____________ issues decades before motor symptoms related to neurodegeneration?
gut/intestinal
synuclein aggregates may be formed in ________________ then get tranmitted to ___________.
enteric neurons; vagus nerve
TRUE or FALSE: vagotomy increases risk of developing PD
FALSE: decrease
TRUE or FALSE: there is evidence that people have gotten PD from ingesting infected tissue
FALSE: only seen in prions diseas
What were the main findings of the study that investigated injection of alpha-synuclein aggregates into the mouse gut?
- mice that did not get synuclein and mice that had a vagotomy did not have any synuclein pathology in the brain
- only WT mice had neurodegeneration
- it is possible for aggregation to start in the gut and travel to the brain
Why is the origin point usually the same for a disease?
VULNERABILITY of certain neuronal/cell populations to protein misfolding and release of aggregates
What are some example of factors that could influence aggregate formation, causing the same origin point for the same disease?
- proteins that are expressed, which allow for initial aggregation
- protein degradation capacity of cell
- activity and environment of cell
Why is the spreading patten usually the same for a disease?
- ARCHITECTURE of cell
- ability of connected neurons to accept and propagate SEEDS
What are the results when PD patients are given a graft of feotal neurons?
- grafted neurons develop Lewy bodies
- spreading process slow (11+ years)
What was the key finding about neuron to neuron spread in the patient who had a tumour removed but then later got diagnosed with AD?
- lesioned region had no tau aggregate pathology
- SPACE/PROXIMITY affects aggregation/spread
What are mechanisms for cell to cell transmission?
- MVB fusion and exosomes (release)
- exocytosis and endocytosis (release and uptake)
- ectosomes
- free translocation
- nanotubes
What is the mechanism for PrP (membrane protein) cell to cell transmission? What is important?
- localization important
- entry into cytoplasm is NOT required for PrP transmission
- PrP has to contact normal PrPc on cells and then infect
(i.e. ENTRY INTO CELL NOT REQUIRED)
TRUE or FALSE: the mouse study that looked at synuclein injection in the gut used SMALLER fibrils and much HIGHER amounts of fibrils, and they waited LONGER
TRUE
