N172 FINAL COMPLETE EXAM QUESTIONS AND
100% VERIFIED ANSWERS
What do lysosomes do?
- phagocytosis: ingestion of foreign cells and also damaged organelles
(mitophagy)
- in the brain, this is primarily done by microglia, but astrocytes can also
phagocytose dead cells
-work best at acidic pH
lysosomes contain many enzymes that allow what?
degradation of a wide variety of metabolites
mutations in each enzyme lead to different diseases
if you lose the fxn of a given lysosomal enzyme, what would you expect
might happen to the waste product it normally degrades?
type of disease depends on what starts to accumulate
lysosomes begin to swell
why are neurons especially susceptible to lysosomal storage diseases?
- neurons can't divide and they can't dilute out the accumulating
substrates
- we don't make new neurons throughout the brain so we can't replace
those that die
Sandhoff's Disease
- lysosomal storage disease
- heterozygous autosomal recessive
- results from loss-of-fxn of an enzyme beta-hexosaminidase leading to
toxic accumulation of GA2 and GM2
-on avg 1 in 4 kids of carrier parents are effected
Sandhoff's symptoms
Symtpoms:
- can appear normal until about 6-months when child starts to show
regerssion of developmental milestones
-muscle weakness, blindness, deafness, inability to react to stimulants,
,respiratory problems and infections, mental retardation, seizures,
enlarged liver and spleen
- most children with sandhoff' die by 3 years of age
current treatments of Sandhoff's
- only symptomatic and supportive treatments are currently available
- supportive treatments includes proper nutrition and hydration and
keeping the airway open
-anticonvulsants may be used to control seizures
Just injecting a replacement of the missing enzyme won't work for the
major neurological symptoms of Sandhoff's. Why?
- enzyme won't cross the BBB
Deletion of Beta-hexosaminidase models sandhoff's disease and neural
stem cell transplantation of neonates improves survival
- NSCs mice lifespan extended by a little
- preserved motor fxn for 16-18 weeks
mouse NSCs integrate robustly into the neonatal Sandhoff's mouse
model brain
- mNSC differentiate into neurons, astrocytoes, and oligodendrocytes
- Transplanted mNSCs increase beta-hexosdaminidase levels and
decrease GM2 and GA2 gangliosides (partial reduction)
- microglial reactivty (sign of inflammation) is reduced in NSC-
transplanted mice
human NSC found similar results as mNSC in Sandhoff's
hCNS-derived and hES-derived (human emmbryonic stem cell) NSCs
also improve survival and motor function + reduce GM2 and GA2
concentrations
why is there only a partial improvement in survival and fxn?
although you doubled Beta-hexosamindase, only were able to go from
2% to 4% which is not enough
also adding NSC that can degrade the buildup, but the other neurons
still can't - cross-correction
cross-correction
most of the lysosomal enzymes travel from the golgi to the lysosome
within the transplanted cells. Only a small proportion of the fxl enzyme is
secreted by the NSCs and taken up by the host neurons
, - some of the enzymes from the NSC are leaking out and getting
endocytosed by the host neuron and goes to lysosomes -> very low in
conc that leak out tho so not as effective
Gaucher Disease
- most frequent lysosomal disease
- 25% of affected child in autosomal recessive
- cell that is most effected is macrophages (a part of innate immunity,
cousin of microglia) which are important for turnover of red blood cells
- in GD, lysosomes are incapable of degrading lipids in RBCs,
accumulation of fat-filled lysosomes
Link btwn GD and parkinsons
patients who are carriers have 4x likelihood to get parkinsons
why? dopaminergic neurons wit heterozygous GBA mutations have
decreased GBA activity, leading to increased accumulation of lysosomes
+ many GD patients see accumulation of alpha synuclein in lewey
bodies
Types of Gauchers
three types:
- type 1: onset typically childhood due to dysfunctional GBA gene most
common type - about 95%) - partial loss of mutation
- type 2: has diff types of mutations in the GBA gene (the most severe)
-type 3: diff mutation in GBA
Most severe type of GD?
type 2
What cells are most effected in Gauchers?
- macrophages
- now can't turnover RBC bc can't break down the RBC lipids
PD patients with GBA mutations exhibit the same symptoms as other PD
patients
- another mutation other than synuclein
making iPSC-models of PD with GBA mutations
- dopaminergic neurons with heterozygous GBA mutations have
decreased GBA activity, leading to increased accumulation of lysosomes
-also have increased numbers of lysosomes with undigested lipids
100% VERIFIED ANSWERS
What do lysosomes do?
- phagocytosis: ingestion of foreign cells and also damaged organelles
(mitophagy)
- in the brain, this is primarily done by microglia, but astrocytes can also
phagocytose dead cells
-work best at acidic pH
lysosomes contain many enzymes that allow what?
degradation of a wide variety of metabolites
mutations in each enzyme lead to different diseases
if you lose the fxn of a given lysosomal enzyme, what would you expect
might happen to the waste product it normally degrades?
type of disease depends on what starts to accumulate
lysosomes begin to swell
why are neurons especially susceptible to lysosomal storage diseases?
- neurons can't divide and they can't dilute out the accumulating
substrates
- we don't make new neurons throughout the brain so we can't replace
those that die
Sandhoff's Disease
- lysosomal storage disease
- heterozygous autosomal recessive
- results from loss-of-fxn of an enzyme beta-hexosaminidase leading to
toxic accumulation of GA2 and GM2
-on avg 1 in 4 kids of carrier parents are effected
Sandhoff's symptoms
Symtpoms:
- can appear normal until about 6-months when child starts to show
regerssion of developmental milestones
-muscle weakness, blindness, deafness, inability to react to stimulants,
,respiratory problems and infections, mental retardation, seizures,
enlarged liver and spleen
- most children with sandhoff' die by 3 years of age
current treatments of Sandhoff's
- only symptomatic and supportive treatments are currently available
- supportive treatments includes proper nutrition and hydration and
keeping the airway open
-anticonvulsants may be used to control seizures
Just injecting a replacement of the missing enzyme won't work for the
major neurological symptoms of Sandhoff's. Why?
- enzyme won't cross the BBB
Deletion of Beta-hexosaminidase models sandhoff's disease and neural
stem cell transplantation of neonates improves survival
- NSCs mice lifespan extended by a little
- preserved motor fxn for 16-18 weeks
mouse NSCs integrate robustly into the neonatal Sandhoff's mouse
model brain
- mNSC differentiate into neurons, astrocytoes, and oligodendrocytes
- Transplanted mNSCs increase beta-hexosdaminidase levels and
decrease GM2 and GA2 gangliosides (partial reduction)
- microglial reactivty (sign of inflammation) is reduced in NSC-
transplanted mice
human NSC found similar results as mNSC in Sandhoff's
hCNS-derived and hES-derived (human emmbryonic stem cell) NSCs
also improve survival and motor function + reduce GM2 and GA2
concentrations
why is there only a partial improvement in survival and fxn?
although you doubled Beta-hexosamindase, only were able to go from
2% to 4% which is not enough
also adding NSC that can degrade the buildup, but the other neurons
still can't - cross-correction
cross-correction
most of the lysosomal enzymes travel from the golgi to the lysosome
within the transplanted cells. Only a small proportion of the fxl enzyme is
secreted by the NSCs and taken up by the host neurons
, - some of the enzymes from the NSC are leaking out and getting
endocytosed by the host neuron and goes to lysosomes -> very low in
conc that leak out tho so not as effective
Gaucher Disease
- most frequent lysosomal disease
- 25% of affected child in autosomal recessive
- cell that is most effected is macrophages (a part of innate immunity,
cousin of microglia) which are important for turnover of red blood cells
- in GD, lysosomes are incapable of degrading lipids in RBCs,
accumulation of fat-filled lysosomes
Link btwn GD and parkinsons
patients who are carriers have 4x likelihood to get parkinsons
why? dopaminergic neurons wit heterozygous GBA mutations have
decreased GBA activity, leading to increased accumulation of lysosomes
+ many GD patients see accumulation of alpha synuclein in lewey
bodies
Types of Gauchers
three types:
- type 1: onset typically childhood due to dysfunctional GBA gene most
common type - about 95%) - partial loss of mutation
- type 2: has diff types of mutations in the GBA gene (the most severe)
-type 3: diff mutation in GBA
Most severe type of GD?
type 2
What cells are most effected in Gauchers?
- macrophages
- now can't turnover RBC bc can't break down the RBC lipids
PD patients with GBA mutations exhibit the same symptoms as other PD
patients
- another mutation other than synuclein
making iPSC-models of PD with GBA mutations
- dopaminergic neurons with heterozygous GBA mutations have
decreased GBA activity, leading to increased accumulation of lysosomes
-also have increased numbers of lysosomes with undigested lipids
