Lysosomes

Question 1

what do lysosomes maintain the homeostasis of?

Answer 1

cholesterol (via npc)

Question 2

how does the membrane of lysosome itself keep from being degraded?

Answer 2

highly glycosolated

Question 3

describe the lysosomal hydrolase’s journey to the lysosome

Answer 3

o In ER N-glycosolation of asp residues o In Cis Golgi GlcNAc phosphotransferase puts 1-phosphate on mannose (catalytic site) by recognizing signal patch o Trans golgi removes sugar (N-acetyl glucosamine), uncovers signal o TGN- m6p receptor binds> clathrin coated vesciles> fuse with endosomes, lower pH environment and m6p receptor releases to be recycled

Question 4

Whats the name of the coat that helps recycle the m6P back from the endosome to the golgi?

Answer 4

Retromer coat is the one that goes from endosome back to TG

Question 5

what are 4 transmembrane receptors responsible for targeting lysosomal proteins?

Answer 5

two m6p receptors (46 forms dimers, 300 has 2 binding sites), sortilin-not m6p modified limp2 (binds bgc)- not m6p modified

Question 6

Lysosomal storage diseases result in how many births? What causes usually

Answer 6

1/5000, can be anything thats related to lysosomal function (i.e. NPC is just a lysosomal transmembrane protein and not an enzyme but can result in disease)

Question 7

Which system is most commonly effected by lysosome dysfunction?

Answer 7

CNS

Question 8

How does gm2 ganglioside usually get degraded? name the enzyme and activator protein and discuss roles

Answer 8

gm2 is stuck in membrane, GM2AP ( w hydrophobic pocket) usually can pick the gm2 out of membrane so can present to hexA to cleave it

Question 9

Tay-Sachs results from what type of mutation, effecting what enzyme?

Answer 9

Hex A gene which produces alpha> HexA activity (ab)

Question 10

Sandhoff results from from what type of mutation, effecting which enzymes?

Answer 10

Hex B gene which produces beta, HexA (ab) and Hexb (bb)

Question 11

AB Variant results from what mutation effecting what protein?

Answer 11

gm2A gene encoding for gm2AP

Question 12

ML-mucolipidoses is a non lysosomal protein…why does it effect lysosomal pathway/cause stuff to build up (i.e. whats its function)

where does this occur?

Answer 12

GlcNAC phosphotransferase deficiency so cant create m6p markers in golgi

golgi

Question 13

MSD-multiple sulfatase deficiency is a non lysosomal protein…why does it effect lysosomal pathway/cause stuff to build up (i.e. whats its function)

where does this action usually occur?

Answer 13

FGE not there so Cys>Glyc cant happen to activate lysosomal sulftatase

ER

Question 14

NPC-Niemann-Pick type C1 , non lysosomal protein causing lysosomal issues…where does this occur and whats the function??

Answer 14

Niemann-Pick type C1 , usually redistributes cholesteral to plasma and ER, gets stuck in lysosome

occurs in lysosome

Question 15

what is the metabolic cross-section type of therapy?

what can you use to replace other than just enzyme therapy?

Answer 15

can take up exogenous enzyme (dont have to replace all just need some) to restore lysosomal activity

can use stem cells or gene therapy to get more good enzyme in

Question 16

Other than giving better enzymes, how can you inhibit accumulation in lysosomes in the first place?

Answer 16

substrate reduction therapy

Inhibit 1st step of glycosphingolipid biosynthesis, reduce production

i.e. Miglustat drug

Question 17

What type of LSD treatment can make sure that less “bad” proteins are sent to the lysosomes?

Answer 17

pharmcological chaperone therapy using reversible lysosomal enyme inhibitors

Question 18

What are the three types of autophagy?

Answer 18

macro-main one, pieces of cyto

micro-intraluminal vesicles w/in lysosome

chaperone mediated

Question 19

What is the CLEAR (coordinated lysosomal expression and regulation) gene network? what kinase and TF are involved?

What else does the TF do to another organelle?

Answer 19

TFEB transcription factor phosphorylated by MTORC1 kinase (LYNUS complex-Lysosomal nutrient sensing, on top of the lysosome)

When starving, kinase stops phosphorylating, so TFEB will enter nucleus and turn on lysosome biogenesis/autophagy to eat self

TFEB also promotes fatty acid beta oxidation in mitochondria

Question 20

How can TFEB overexpression help disease?

Answer 20

promotes cellular clearance can help w liver, neuro, obesity, LSDS’s