Cell biology of disease Flashcards
What size are lysosomes?
Vary in shape but roughly 200-400nm
Which cells are lysosomes found in?
All except red blood cells
What percentage of the cell volume is occupied by lysosomes?
1%
What are the roles of lysosomes
Macromolecules degradation
Plasma membrane repair
Act as secretory organelles in immune cells
How many types of macromolecules does the lumen of a lysosome contain?
> 45
What is the role of hydrolases
The break covalent bonds via hydrolysis so digest macro molecules into their component parts
What is the pH of the lysosomal lumen and how does this compare to the cytosol
Lysosomal lumen= 4.5-5.0
Cytosol = 7.2
How is the pH of the lysosomal lumen maintained
The vaculoar proton pump
This pump transports protons into the lumen
The proton transport is energised by ATP hydrolysis
Name the 3 ways in which materials destined for degradation are delivered to the lysosomes? And what types of molecules are transported by each system
Endocytosis = extra cellular molecules in the fluid phase and PM proteins Autophagy= molecules in the cytosol and whole organelles Phagocytosis= Large extra cellular particulate species e.g microbes
What important role do lysosomes play in receptor signalling
May degrade receptor/ ligand by endocytosis
What is macroautophagy?
Is the best characterised form of autophagy
It involves the envelopement of cytoplasmic materials by a double membrane that fuses with the lysosome delivering its contents. The double membrane may be donated by the PM, ER and or mitochondria
How is macroautophagy enhanced by starvation of cells?
mTOR regulates macroautophagy
In starvation cells you get Rapamycin
Rapamycin inhibits mTOR and therefore promotes macroautophagy
Rapamycin has also been reported to promote clearance of soluble Huntingtin and huntingtin aggregates in mice and also for mutant forms of alpha-synuclein (associated with Parkinson’s)
Describe the role of lysosomes in apoptosis triggered via pathogen/DNA damage?
Increase permeability of membrane of lysosomes
This results in the release of lysosomal proteases, cathepins into the cytosol where they act on cellular targets
Cathepins although not at their optima pH can cleave proteins at cytosolic pH and can trigger the mitochondrial/intrinsic pathway of apoptosis potentially via Bid
However exact role is unclear, likely that cathepins amplify apoptosis
Lysosomes in PM repair
Lysosomes act as a reserve of membrane
Lysosomes excocytosis is triggered via Ca2+ into the cell, which is detected by the lysosomal membrane protein synaptotagmin 7
Lysosomal storage diseases overview
> 50
They are caused by defectes in the degradative function of lysosomes
They are so called due to the abnormal accumulation of molecules within the lysosome.
The accumulation process is poorly understood
I-cell disease: clinical symptoms and genetics
Also known as mucolipididosis type II
An autosomal-recessive disorder
Mutation in the gene (GNPTA) that encodes enzyme N-acetylglucosiminidase-1-phosphotransferase.
Disease is so called because of the formation of Intracellular inclusions
clinical symptoms: Facial abnormalities, skeletal abnormalities, severe psychomotor retardation and heart failure occurs in decade of life
No cure, treatment is limited to reducing symptoms
Molecular basis for I-cell disease
Cells have reduced Intracellular levels of lysosomal hydrolases, but conversely secrete these enzymes into the culture medium.
The enzyme is localised to the cis-Golgi and modifies the mannosylated glycans that are attached to newly synthesised lysosomal hydrolases.
The resultant mannose-phosphate groups are recognised by the mannose-6-phosphate receptors in the trans-Golgi network, which sort lysosomal hydrolases to Endosome and hence to lysosomes
If the hydrolases are not modified by the enzyme they are not recognised and instead secreted by the cell
The result is that lysosomes are deficient in key hydrolases and so impaired in their ability to degrade molecules
Pompe disease: clinical symptoms and genetics
Autosomal recessive mutation in the gene that encodes the lysosomal hydrolase alpha-D-glucosidase
Clinical symptoms: progressive cardiac and skeletal myopathy (disease of muscle) In infantile onset pompe disease death usually occurs within 1st year of life due to cardio respiratory failure
Pompe disease: molecular basis
Glycogen normally stored and hydrolysed in the cytosol, but small amount enters lysosomes
Lysosomal alpha-D-glucosidase cleaves glycogen into glucose that can then transport to the cytosol
Deficiency in alpha-D-glucosidase causes the abnormal accumulation of glycogen in cells and the resultant symptoms of disease.
Can be treated with enzyme replacement therapy: intravenous infusions of mannose-phosphate modified alpha-D-glucosidase is given to patients. This is only effective in cardiac muscle
Fabry disease: genetics and clinical symptoms
X-linked disorder that results from mutations in alpha-galactosidase
Clinical symptoms: Facial abnormalities, wide range of non specific effects that include renal and cardiac problems due to problems in the vasvulature, progressive organ and tissue damage= reduced life expectancy to 40 years but can be increased to 50 with treatment for renal failure
Symptoms due to the deposition of glycolipids globotriaoslyceramide in the wall of capillaries, kidney tubule and glomerular cells, nerves and dorsal root ganglia
Fabry disease: molecular mechanism and treatment
Alpha-galactosidase removes terminal galactose from the glycolipids globotriaoslyceramide (Gb3)
Lack of alpha-galactosidase activity results in accumulation of (Gb3) and lysosomes and lipid droplets in many types of cells
Treatment: enzyme replacement thermal is used to treat fabry disease, with the administration of mannose phosphate form of the enzyme
Infantile Salic acid storage disease (ISASD): genetics and clinical symptoms
Autosomal recessive mutation in the sialin gene
Clinical symptoms: facial abnormalities, mental retardation, enlarged heart, liver and spleen, patients normally die within 1st to 2nd years of life
Salla diease: genetics and symptoms
Caused by a mutation in sialin like ISASD but is less severe, it is found in the Finnish population. But results in physical and mental impairment and life expectancy is reduced to 50 years
ISASD and Salla disease: molecular basis
Sialin is a lysosomal membrane receptor, it transports sialin acid from the lysosome into the cytosol
Sialic acids are 9 carbon monosaccharides that are amongst the breakdown produces of glycolipids, glycoproteins and glucosaminoglycans.
The loss of sialin transport activity results in the accumulation sialin acid in the lysosomes
