Understanding Lysosomes and Their Role in Lysosomal Storage Disorders

hi ninja nerds in this video today we're going to be talking about the function of lysosomes and then the

lysosomal storage disorders before we get into this video please hit that like button comment down the

comment section and please subscribe also down in the description box with links to our

facebook instagram patreon account go check those out all right engineers let's get into

it all right ninja so when we talk about lysosomes we talked a little bit about

them their overall kind of design their structure their basic function in the video on the

structure and function of this of the cell but what we need to do is kind of dig in a little bit deeper into the

lysosomes and what they do the reason why is if we understand the function of lysosomes in a little bit

more of a greater detail it's much much easier to understand the lysosomal storage disorders

so let's start off talking about how lysosomes work well the first thing that you need

to know before how lysosomes work is how they're actually made we briefly talked about this in the structure and

function of the cell but if you remember we start off when we're making

proteins because that's what pretty much the components of lysosomes is these enzymes

and enzymes are proteins so we start off with remember the dna what does it call whenever you go from

dna to mrna it's called transcription so we take and we make

mrna from dna via the process of transcription in the nucleus then out of the nucleus what happens it

moves via the nuclear pores and binds with the particular structure out here which is called a

ribosome the ribosome will then begin to translate parts of that protein let's represent that as like this brown thing

coming out this portion of it so it's translating the mrna and making proteins

what happens is this ribosome will get then kind of like a magnet sucked onto the rough endoplasmic

reticulum so you see this structure here that's this maroon organelle here this is called our rough

endoplasmic reticulum the mrna will get translated into proteins taken up into the rough

endoplasmic reticulum you know what the rough yard does it pushes

this protein once this actual ribosome moves over to the rough er so look here's going to be our

mrna right there it's getting translated and it's translating this protein into the rough er

as it goes to the rough er let's imagine here is going to be our protein you know proteins are special

because on one end they have a amino end and on the other end they have a

carboxylate and all the little components that make them up are called amino acids what the rough er does is it

folds this protein in a particular way and then you know what else it's really important this is very relevant

it takes a particular enzyme and uses the enzyme in the rough er and adds on a sugar residue

to this amine group of the protein you know what this little sugar is called it's called mannose it's called a

mannose sugar but this process by which the rough er adds the mannose sugar onto the

in structure the nitrogen of the protein is called in linked glycosylation what is this

called in linked glycosylation this is a very special

activity that the rough endoplasmic reticulum performs then

after it does this process it then packages that actual protein with this mannose

sugar into a vesicle look at this vesicle here's that vesicle coming off of the rough endoplasmic

reticulum what's going to be inside of it you're going to have your protein

and what's going to be coming off the in the nitrogen of that actual protein a sugar residue right the mannose group

now from the rough er we have to send this to the golgi very important especially for us usm

release step one there's very important proteins that are found on these vesicles going

from the rough endoplasmic reticulum towards the golgi

what are these proteins they guide this like a magnet like zoo right to the golgi what are these called

these proteins that guide this vesicle to the golgi are called cop two proteins cop2

proteins they bind to the vesicle of the rough er and take it to the golgi now

in the golgi this protein with the amino sugar gets kind of budded into this so here we're going to

have that protein right there and then again what's coming off of that protein off the nitrogen

the mannose this actual golgi what is this organelle here this is called your golgi

it does something very special everything does something special i guess right

let's again take our protein here we have it we're going to the golgi as you go to the golgi the golgi does

something else it adds a phosphate group onto this mannose sugar so here let's actually

draw kind of our protein here here's our protein we have the carboxylate here we have the nitrogen in

here and then again what's coming off of this you're going to have your

mannose sugar and then off that manual sugar what does the golgi add on here let's actually do a

special color here let's use orange what the golgi does is is it actually adds in

a phosphate group you see this phosphate here we're gonna add this into this reaction

and then what we're gonna do is we're gonna add this phosphate onto the mannose sugar on the sixth carbon of it

this is a very important reaction this is called phosphorylation right this is called phosphorylation

the reason why this is important for your usmles step one is because there's a disease called eye cell

disease it's called eye cell disease and this disease is usually whenever the

golgi is unable to add a phosphate group onto the mannose of proteins

and so because you don't have that phosphate why is that important why am i stressing on that here's why

from the golgi guess what in order for these vesicles to butt off and become lysosomes so from the golgi

we're going to butt off a vesicle and we want those vesicles containing this protein to become a

lysosome we need this phosphate group onto it if that phosphate group is not

on that mannose of the protein we will not make functional lysosomes enzymes so because of that we need that actual

phosphate to be there if it is not we will not make lysosomes that is why it's important

okay so now to quickly recap we took mrna we translated into proteins stuffed it

into the rough er it added a sugar residue used the cop2 to send it to the golgi

golgi then added a phosphate onto the mannose that phosphate when it's added onto the mannose sugar that's bound to

the glue to the actual protein molecule it's then destined to become

lysosomes if that process of phosphorylation does not occur this is called

eye cell disease okay we've made our lysosomes once we've made our lysosomes we now

need to know what the heck these little buggers do there's very important processes called

endocytosis so what is this called endocytosis endocytosis is the process by which you bring

substances or macromolecules into the cell there's two main types that are

important with respect to the lysosomes the first one is called phagocytosis so it's called phagocytosis

and this is very very important within your white blood cells you know macrophages

neutrophils which are your white blood cells they love to engulf take in what types

of things pathogens what is a very very dangerous pathogen like one of them there's many

of them but one that we encounter is bacteria and what happens is these bacteria can

get engulfed by white blood cells like macrophages and neutrophils and brought

into the cell when they're brought into the cell via this process of phagocytosis guess what it does

it takes and actually creates a little vesicle what like an endosome if you will and

this endosome contains the bacteria in it now this actual endosome when it's with

respect to phagocytosis it's given a special name it's called a phagosome

it's called a phagosome what happens is that phagosome which contains the pathogen what type of

molecule in here it contains the bacteria it then gets combined with a lysosome what are these

molecules these are called your lysosomes once the lysosome combines with the

phagosome now look at this we're going to have here's the lysosome with all these nasty

little enzymes and then over here we're going to have the phagosome which combines

and it's going to have the bacteria here's what i want you to remember these lysosomes contain very dangerous enzymes

we already talked about how we synthesize these enzymes but we need to talk about what these enzymes

are they contain very nasty hydrolytic enzymes that just means it breaks down

substances by adding water into it and these hydrolytic enzymes they can be proteases

nucleases lipases glucosidases which means it breaks down proteins carbohydrates nucleic acids and

lipids you know what a bacteria is made up of all those macromolecules

so guess what the lysosome will do it gonna frick it up it's gonna come in there and start

breaking down the proteins the nucleic acids the lipids all of that stuff until it's all

digested that is what the lysosome will do so the lysosome will

actually do what it'll break down the bacteria and then in certain cells like

neutrophils guess what that'll do with that lateral lysosome which contains all the

broken down maybe remaining products it'll then take and spit it out of the cell

so that's one thing that you need to know with the lysosomes very important when it comes to these white blood cells

the next one is called receptor mediated endocytosis what the heck is that that's a big name right

receptor mediator so we need an example of a receptor and then a molecule that binds to that receptor

the most classically used examples is ldl which is a lipoprotein bad cholesterol

and then there's a particular molecule that that ldl binds to the ldl receptor pretty straightforward right

this happens on the liver when ldl binds onto this ldl receptor in the liver there's little proteins you know these

these special little proteins called clathrins what are they called here we're going to

put look at a c these are called clathrins and what the clathrin molecules do is they bind to the

membrane which has the ldl receptor and the ldl bound to it and creates a little invagination called

a clathrin-coated pit then it continues to pull pull pull pull until it invaginates and creates a

vesicle or an endosome so then look what will happen as a result of this through this process of what is it called

receptor mediated endocytosis we're going to take in this little structure here

so now we're going to have a vesicle and that vesicle is actually going to be called a

endosome that's what we like to call it an endosome just like a phagosome is an endosome

it's just a special name from the process of phagocytosis what does the endosome contain within it

it has the ldl receptors and then it also has the ldl molecules bound to it

guess what happens with this endosome the endosome has little like pumps on it little proton pumps

and these little proton pumps they start pushing in lots of protons making this environment very

acidic you want to know what that protons do whenever they get pumped into this

environment they make the bond between the ldl receptor

and the ldl very weak so that they disassociate from one another so then as a process of

this look what will happen as a result of this as the protons get pumped in look at

this let's kind of see what happens here you're going to get kind of like a

little bubbled vesicle here like a little bubbled one here right

and then what happens is as the process of these protons coming in it separates the ldl receptors

away from the ldl molecules then after that process guess what happens we pinch this off

and separate this into two separate vesicles so now we're gonna have that and we're gonna have this and then

you're going to have this vesicle here which contains the ldl receptors and this vesicle here which is going to

contain the ldl molecules guess where the ldl molecules will go

well they're a type of macromolecule they will get sent to this lysosome and when they get sent

to the lysosome guess what they're going to do the lysosomes contain specific types of

lipases and sphingomyelinases and all these different enzymes that'll break down the cholesterol the

phospholipids the proteins all of the stuff within the ldl molecule

so what else will break down not just the bacteria but it'll also break down in this

example since we're using this example the bacteria and the ldl particle the question is what the heck happens to

this little receptor here just to finish the story because i know you guys are begging to know what

happened right you know our cells are so cool you know what they do with these ldl molecules

they send them to get recycled so they get recycled and sent right back to the cell membrane to

rebind into the plasma membrane and express these ldl receptors so that the next ldl combined

bring it in and do the same process now again you need to understand what the fate is

of this lysosome we understand it breaks down macro molecules from

a particle matter via phagocytosis or breaks down macromolecules from receptor mediated

endocytosis once it breaks all these things down the important thing to remember is

what happens with this actual lysosome so let's say it's performed its function it's broken down all these

macromolecules and bacteria once it's done that it's called a secondary

lysosome there's two things that can happen with this secondary lysosome it can spit some of

these molecules out into the cytosol that maybe can be used for certain metabolic pathways

or you know what else it can do it can go to the cell membrane

bind with the cell membrane and release some of these molecules out of the cell via a process called exocytosis

so now you guys should understand with a quick quick recap lysosomes break down macromolecules

within a bunch of different ways right primarily via these hydrolytic enzymes it can break down macromolecules

for the process of phagocytosis break down molecules from the process of receptor immediate endocytosis

after it breaks it down it can spit some of these molecules out into the cytosol or it can spit it out of the cell via

exocytosis the last thing you need to know about the lysosomes sometimes our cells we have organelles

that they just reach their prime they're kaput they're old geezers they're done

like mitochondria and specific types of proteins within the cell when these things have been worn out

let's actually kind of let's tag them as that we're going to say that these are

worn out organelles okay or different you know protein elements whether it be mitochondria

cytoskeletal structures whatever when they're worn out they get tagged with like specific molecules

and you know what this tag does it says hey these these organelles are done it's time for

them to go so our cell creates a little membrane around them

it creates a little membrane around it so now i'm going to have a membrane around these organelles

so what will i have in here well my example was i had a mitochondria and then i also had a protein molecule

here what happens is once you do this you take and engulf your own organelles that

are done worn out this is called a auto phagosome

it's another type of endosome this autophagosome guess what it's going to do

it's going to get taken to the lysosomes and when it gets taken to the lysosomes

guess what the lysosomes are going to do they're going to break down the mitochondria what's the mitochondria

made up of it has lipids it has proteins it even has a little bit of nucleic acid in

there it's going to break all that down it's going to break down the protein elements

all of that stuff will get broken down so not only does it break down bacteria and ldls

but this process by which can break down worn out organelles what is this called this process is called we're going to

note it up here this process where we break down these elements here this is called auto

phagy very important process this is very important so that we understand the function of lysosomes now

that we understand the function of lysosomes how they carry out these activities

now let's talk about lysosomal storage disorders whenever these normal functional pathways

aren't occurring normally all right so we know that lysosomes have these very nasty hydrolytic enzymes

right so if we took a look at these lysosomes we understand that these lysosomes

release a lot of hydrolytic enzymes and again there's different kinds like lipases

there's what's called uh proteases nucleases and these are just like the broad category of them there's

glucosidases and there's many other different types of enzymes but these are your hydrolytic

enzymes and they're responsible for breaking down macromolecules so again these are just

the general understanding of your hydrolytic enzymes the reason why all of this is important is that there's

genetic conditions in which the lysosomes aren't being able to break down

those macromolecules whether it be a lipid a protein a nucleic acid or a sugar molecule

and that leads to these common diseases which are very high yield for u.s emily step one

what are some of these well one of them is tay sachs disease now taste accident has a particular enzyme a particular

hydrolytic enzyme that as you can see here i have the shape of him which is going to tell you

pretty much the actual enzyme this enzyme is called hex aminodace

a this hexaminodase a is responsible for breaking down a particular type of macromolecule

and this macromolecule is called a gm2 ganglioside ganglioside why is this important if there is a

deficiency or loss of this enzyme there is an accumulation of this gm2 ganglioside

if that gm2 ganglioside that substrate macromolecule builds up in particular tissues

it's going to cause damage to that tissue another important fact here is that this

disorder this tay sachs disease is autosomal recessive okay it's autosomal recessive

so you need two mutant copies in order to have this condition now what tissues does this gm2

ganglioside usually accumulate within the primary area that it accumulates in is in the central nervous system and as

these actual gm2 gangliosides accumulate within the central nervous system it leads to

progressive newer neurodegeneration so it's going to lead to neuro degeneration

and this neurodegeneration is the classic sign that you're going to see now what are some of the ways that we

can see this neurodegeneration well one of these ways is hyperreflexia so

increase deep tendon reflexes that's one big one another one is called hyperacusis where

they have very very uh like sensitivity to hearing very pain a very sensitive intense

sensitivity to hearing and the other one here is they have seizures

because of these deposits within the tissue and here's a very big fact on the retina they have an accumulation

of this tissue near the macula and this leads to what's called a cherry red spot on the

macula near the retina that's an important fact now lysosomes are very very abundant

and are actual what's uh what types of tissues well obviously white blood cells is a big one but what do we notice was

another one the liver here's one big thing that you need to remember tay sachs disease

is one of the few lysosomal disorders where there is no hepatomegaly as you can see most of

these have livers around them this one has no hepatomegaly

and the reason why i want to under help you guys to understand this is that usually taste accesses and neem

and pick disease can somewhat present similarly but one of the big differences between tay sachs

and neiman pick is that there is no hepatomegaly in taysac's disease

all right beautiful we know we understand taste axes hexadeficiency accumulation of gm2 ganglioside

autosomal recessive neurodegeneration no apatomegaly what about the next one

fabrics disease fabry's disease is actually a deficiency or a loss of alpha galactosidase so what is this

enzyme here called it is called alpha galactosidase alpha galactosidase breaks

down one heck of a sun of a gun of a substrate and this substrate is called

ceramide trihexacide trihexacide so in this condition which this condition is autosome sorry

x-linked recessive this is x-linked recessive so you're going to see this more commonly in what

sex male or females male so in this disease there is a mutation where there is a loss of alpha

galactositis which creates an accumulation of serum trihexacide within particular tissues

what are these particular tissues this one's a son of a gun so i tried to find a mnemonic for these

ones and the big thing that you can remember is fabry

c fabry c so f for foamy urine and that helps you to remember that this is usually due to

kidney failure okay so this will usually be due to the renal failure okay that's the first one the second one

is a and this is for angiokeratoma angio keratomas these like

little red spots that you can develop within the skin b is for burning pain

in the hands and the feet this is indicative of neuropathy r is for really dry

skin really dry skin and this is indicative of a condition where you don't make a lot of

sweat called hypohydrosis the next one is that this is only going

to be seen in males only males have a y chromosome and the last one here is that it's also

going to be accumulating within the heart tissue and this leads to cardiovascular

disease this is fabric disease deficiency or loss of alpha galactosidase accumulation of ceramide

triaxide excellent recessive foamy urine angiocarotoma burning pain really dry skin

only really seen in males and cardiovascular disease boom roasted let's move on to the most

common gaucher's disease all right the next one this is going to be the most

common lysosomal storage disorder so therefore that's a very important thing that you guys need to remember

this is the most common lysosomal storage disease now again there is an accumulation of a

particular substrate due to the loss of a particular hydrolytic enzyme that hydrolytic enzyme

you can remember beta glucosidase but the other name for it is called glucosere

the only reason i say this one is because guess what the substrate's name is

it's called gluco cerebro side so in this condition which is autosomal recessive an easy way to

remember these is that all of them are autosomal recessive except for fabries which is excellent recessive

this is autosomal recessive in this condition there is a loss of

glucocereprosidase or beta glucosidase and therefore an accumulation of glucose cerebroside within the particular

tissues what tissues does this glucose cerebroside like to accumulate in the bone tissue you know particular

portion of the bone tissue that's very important the red bone marrow guess what happens

if this kind of accumulates within the bread bone marrow and affects the activity of the red bone marrow

what does the red bone marrow make it makes red blood cells it makes white blood

cells and it also makes platelets if these accumulate it's going to damage the red

bone marrow what's going to happen to the number of platelets decrease red blood cells

decrease white blood cells decrease what is this called pancytopenia pan cyto

that's one thing the other thing is that can it can actually accumulate within the bone

and lead to bone infarctions which is called a bone crisis so it can lead to a vascular necrosis of the bone

and the other thing is if this is actually continuous over time it can lead to

early onset osteoporosis so it can also really damage the bone tissue and lead to

osteoporosis the next thing is if these little molecules these glucose cerebrosides

accumulate within the liver and accumulate within the spleen guess what this is called

this is called hepatosplenomegaly this is called apato and then for the spleen this is called

splenomegaly very very important for these the next thing

this is a very very high yield very commonly asked on the usmle step one you remember we said that macrophages

are very important because they contain lysosomes that break down a lot of bacteria and substances

if these glucose cerebroside molecules accumulate with inside of the macrophages it produces a

very classical type of cell we call these cells gaucher cells you can see this under microscopy and

it's basically where the glucose cerebroside which is a type of lipid these are all what's called

sphingolipidosis if this accumulates these lipids it leads to lots of lipid inclusions

accumulating within these macrophages and this is called gaucher cells and where they love to be

found the spleen the liver and in the bone tissue

okay the last one which is neem and pick disease now neiman pick disease is actually again an autosomal recessive

disorder so again what is this disease this is autosomal recessive again all of them are autosomal recessive

except for which one again fabrics which is excellent right and you can remember the mnemonic

because they only have a y chromosome in males now the particular enzyme hydrolytic

enzyme that is actually going to be lost in this look at this little dude this is shaped like an s this is called

sphingosphingo myelinase this enzyme is absent or super deficient and therefore

not able to break down the particular substrate it breaks down which is called oh thankful thank goodness it's a super

super simple one sphingo myelin so in this autosomal recessive disorder where you have no

sphingomyelinase you don't break down sphingomyelin and it accumulates within particular tissues what are the

particular tissues it accumulates in remember we said this is very similar to tay sachs disease

the only thing that's different with tay sachs is that it does not have hepatomegaly so in that case we already

can answer these two quick ones here it accumulates within the

liver and within the spleen what is this called collectively whenever they get enlarged because of that accumulation

it's called hepato splenomegaly the next thing that's important here it also

loves to accumulate within the brain tissue and when it accumulates within the brain

tissue it leads to neurodegeneration so again you're going to see that neurodegeneration

but here's the big thing here we remember in the tay sachs there was hyperacusis

hyperreflexia and there was even um some of that cherry red spot

this has some of the similar features it's still going to have like seizures and developmental delays but the big

thing here is it also has a cherry red spot that accumulates on the macula within the retina so which ones

both have cherry red spots name and pick disease and taste axe disease what's the big difference

between them the tay sachs has no hepatomegaly and neem and pick disease has

hepatosplenomegaly one more thing that you need to know phrenompic disease is that again

macrophages are important for you know they have lots of lysosomes to break down certain bacteria

if these sphingomyelin molecules accumulate it's going to produce again a lot of lipid inclusions that

accumulate within these macrophages so these are called whenever they have a lot of these lipids

they love to call these remember how these were called gaucher cells they love to call these foam cells

foam cells one other important high yield fact is if you have these when you're comparing these two because

you're like oh wow this has a lot of lipids this has a lot of lipids how do i know

the difference well one thing is the dependent upon the substrate but

here's another thing they got to try to make it a little easy when you look at this under a microscope

gaucher cells look like crumpled [Music] tissue paper and that is a very

important thing to remember for your u.s emily step ones so again crumpled tissue paper gaucher

cells lots of lipid accumulation in foam cells these are going to be the

name and pick disease types of macrophage accumulation with lipids so again that covers the lysosomal

storage diseases iron engineers in this video we talk about lysosomes and lysosomal storage

disorders i hope this made sense and i hope that it helped all right ninja nerds as always until

next time [Music] you