Lecture 14: Lysosomal Storage Disorders Flashcards
What percent of lysosomal storage disorders does Sandoff account for?
2%
What do lysosomes do?
Lysosomes are cellular organelles that break down large waste products of metabolism, damaged organelles, or foreign particles/cells.
“Trash man of cell”
Get rid of big aggregates
Part of autophagy leads to lysosome fusion and degradations.
Immune cells also fuse to lysosome for degradation after going through proteasome.
Lysosomes contain many ___ that allow degradation of a wide variety of ___
1) enzymes
2) metabolites
Mutations in each of these ___ lead to different diseases.
1) enzymes
Describe how different mutations in the enzymes can lead to various diseases.
Having one normal gene is enough.
Most of the diseases are homozygous recessive.
When disease arises it is usually a loss of function mutation disease.
If you lose the function of a given lysosomal enzyme what would you expect might happen to the waste product it normally degrades?
The further up this pathway that a lysosomal enzyme loses function, the more severe the disease because it depends on accumulation of what isn’t degraded.
___ percentage of diseases affect the nervous system particularly neurons.
95%
Why are neurons especially susceptible to lysosomal storage problems?
This is because cells that divide are less susceptible to this because they divide and “split” the trash more.
Neurons don’t divide, and thus are more vulnerable.
____ Disease is one example of a lysosomal storage disease
Sandhoff’s
Many of the diseases are ___
pediatric (Occur in ages 6-9 months depending on disease).
What goes wrong in Sandhoff’s disease?
In Sandhoff’s disease there is a problem with the function of an enzyme called Beta Hexosaminidase
It occurs through autosomal recessive inheritance.
(Need two faulty genes).
It results from loss of function mutations in Beta Hexosaminidase leading to a toxic accumulation of the gangliosides: GA2, GM2
What are symptoms of Sandhoff’s disease?
Can appear normal until about 6 months when child starts to show regression of developmental milestones.
Muscle weakness, blindness, deafness, inability to react to stimulants, respiratory problems, and infections, mental retardation, seizures, enlarged liver and spleen.
Enlarged liver and spleen= red blood cells aren’t degraded.
Most children with Sandhoff’s die by 3 years of age.
What are current treatments for Sandhoff’s?
Treatment approach: enzyme replacement
Only symptomatic and supportive treatments are currently available.
Supportive treatments includes proper nutrition and hydration and keeping the airways open.
Anticonvulsants may be used to control seizures.
If you could replace the missing enzyme that ought to cure the disease!
Gene therapy: use virus to deliver the gene you need.
Promising in animal models but hard to get it to spread throughout the brain.
Just injecting a replacement of the missing enzyme won’t work for the major neurological symptoms of the disease why?
This is because the enzyme won’t cross the BBB.
Approachs:
Canula Method
Doesn’t diffuse through whole brain.
Stem cells act through multiple mechanisms to benefit mice with _____
neurodegenerative metabolism disease.
Knockout Beta Hexosaminidase to model it in mice.
Deletion of ____ models Sandhoff’s disease and ____ of neonates improves survival.
1) Beta Hexosaminidase
2) Neural stem cell transplantation
How easy is it to have drugs that mimic enzymes for genetic diseases?
Genetic diseases are too complicated to have drugs that mimic enzymes.
