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intra and extra cellular accumulations leading to human diseases…
intra and extra cellular accumulations leading to human diseases
intracellular accumulations
where?
cytoplasm
organelles
nucleus
what?
normal cell constituent
water
vacuolar degeneration
lipids
hepatic steatosis
due to alcohol consumption, starvation, protein malnutrition
foam cells in atherosclerosis
proteins
hyaline droplets in nephrotic syndrome
Russel's body in highly activated plasma cells
glycogen
poor controlled diabetes, proximal tubule
endogenous pigments
haemoglobinogenic
hemosiderin
bilirubin
non-haemoglobinogenic
melanin
lipofuscin
endogenous substances due to faulty catabolism or degradation
hereditary Mendelian diseases due to specific enzymes deficiencies
classified based on the material that accumulates
glycogenosis
sphingolipidosis
...
affect
CNS, liver, muscles
shortened life-expectancy, affected quality of life
abnormal endogenous substance
proteins
Huntington's disease
Lewy's bodies in Parkinson's and demetia
misfolded proteins
ER stress and the unfolded protein response
abnormal exogenous substance
pathologic calcifications
dystrophic calcification
at site of cell injury and necrosis
necrotic tissue
advanced atheroma
haematoma
thrombus
infarction
heart valves (endocarditis)
metastatic calcifications
in normal tissue, caused by hypercalcaemia
extracellular accumulations
protein misfolding disease
misfolded proteins
non-functional
thermodinamically unfavourable and unstable
tendency to aggregate
1- nucleation - proteins attach reversibky to a growing core
2- once it is reached a critical mass, proteins attach irreversibly
structure varies from unorganized to hoghly ordered fibres called amyloid
the fibrillar deposit binds proteoglycans and GAGs
amyloid
common secondary composition - coss-beta structure
8 classes
parallel/antiparallel
face-to-face/face-to-back
up-up/up-down
it is not a single chemical entity
amyloidosis
systemic amyloidosis
hereditary amyloidosis
localized amyloidosis
cellular mechanisms of toxicity
aggregates insert inside the phopsholipid bylayer, disrupting membranes. they form amphiphilic micelle-like aggregates, causing membrane permeabilization
common pathogenesis of neurodegenerative disorders
crystallopathies
aberrant crystallization occurs sometimes and cause diseases
particle size is a critical determinant of crystal handling by phagocytes
amourphous solid
phagocytosis
cristalline solid
depending on the measure: phagocytosis/frustrated phagocytosis
polycristalline solids
frustrated phagocytosis
mineral solids form during homeostasis or execretion
predominant pathologic mechanism
acute necroinflammation
chronic tissue remodelling
obstruction by crystal masses
mechanisms of crystal induced inflammation