This is gonna be our final podcast on the cytoskeleton and here we're going to
talk about the intermediate filaments. Intermediate filaments are a
heterogeneous group of cytoskeletal molecules. They're found in all the
cell's. The intermediate filaments are structurally very stable so unlike
microtubules and microfilaments which are dynamic, intermediate filaments are
highly stable structures. They have a high tensile strength,
they're almost like cytoplasmic ropes. They're ten nanometers in diameter.
Most consists of 50 kiloDalton subunits. The subunits are nonpolar, they
are highly variable intermediate filaments tend to be tissue specific so
for example we talked about cytokeratins as uniquely representing epithelial
cells. Microfilaments form a continuous link with the cytoplasmic, nuclear, and
extracellular matrix filaments and the cartoon here would just show these
intermediate filaments that are running throughout the cytoplasm of cells and
you might imagine these intermediate filaments give sheets of cells
tremendous rigidity against lateral shear forces and that's meant to be
highlighted here, the intermediate filaments are going to stretch and
distribute applied forces throughout the cell and they're gonna make these cells
be held together very rigidly in sheets of cells and you might imagine for
example that if you had cells that were just attached at rivet points on their
membranes if there were shear forces these cells would easily split apart. On
the other hand think about the filaments. It's like rebar that are running through
concrete, they really reinforce the cells and give tremendous rigidity to cells
where the sheet of cells would be subjected to lateral shear forces.
There's a mutation in a keratin gene that leads to epidermolysis bullosa. You
get a lot of blistering, the sheets of cells don't hold together
because of a mutation in a keratin gene which is necessary for the stability of
these keratin intermediate filaments. Here just gives you an idea of the
structure of intermediate filaments. There's a highly variable central region
that's kind of like a rod shape and this is why we say the intermediate filaments
are very variable and they're almost unique to different tissue types but
there's also highly conserved globular regions at both the N terminal and C
terminal ends of these molecules. Now these intermediate filament monomers are
going to twist around each other in a parallel manner and form a dimer type
structure but then two dimers are gonna twist around each other in a staggered
and anti parallel manner to form a tetramer and then the tetramers as
individual units are gonna align along the long axis of the filament to form
these very stable rope-like structures and here you can see them in the
electron micrograph and then just diagrammatically like this. Intermediate
filaments can be organized into six major classes that are based on gene
structure, protein composition, and cellular distribution. This is a fairly
complicated slide I've put in blue font what I think is important for you to
remember visa vie intermediate filaments. Now there are six classes as
we said, classes 1 and 2 are the keratins. These are the most diverse group of
intermediate filaments. They're found in virtually all epithelial cells, in humans
there are at least 50 different types of keratins and perhaps almost 50 different
types of genes that code for these keratin intermediate filaments. Class 1
keratins are so-called acidic keratins, class 2 keratins are the
so-called basic keratins or cytokeratins. Keratins also have three expression
groups. There are those that are found in simple epithelia, those
found in stratified epithelia and those that are considered the hard keratins
and you know the hard keratins as the protein subunits of hair and nails. Class
3 intermediate filaments of vimentin and vimentin-like proteins. These the
most widely distributed intermediate filaments in the body.Vimentin is found
in cells of mesodermal origin so they're found in endothelial cells, they're
found in some smooth muscle cells and in some cells of the neural ectoderm,
desmin another intermediate filament found in most muscle cells, glial
fibrillary acidic protein found in neuroglial cells and schwann cells and
peripherin found in axons of peripheral neurons. Class 4 intermediate
filaments on neurofilaments that are expressed in axons. There are several
types of these that are called neuro filament low weight, neuro filament
medium weight, neuro filament high weight. You don't really have to necessarily
remember those but those are the neuro filaments that are expressed in axons.
There are other classes of intermediate filaments that are so called neuro
filaments that are expressed in neurons and some of them are actually even
expressed in muscle. Class five intermediate filaments of the lamins
these are expressed in all nucleated cells, you know these as the nuclear
lamin proteins. There's lamin A and C which are important in maintaining the
integrity of the nuclear envelope and lamin B to which the lamin A's and C's
interact and help to form the nuclear pore complexes and then as the Class six
intermediate filament proteins, these are specific to the lens and I don't care
that you necessarily remember these right now for our course, but this cartoon
just highlights the classes of the intermediate filaments so we can talk
about intermediate filaments, the keratins that are uniquely found in
epithelial cells so class one and class two intermediate filaments of keratins.
This is important clinically because if you've got a tumor of unknown origin
you can do cytochemical stains for the various intermediate filaments and know
where the tumor comes from so for example if you've got an undefined tumor
that stains positively for keratin you know that that tumor would be from an
epithelial origin tumor. Vimentin and vimentin-related proteins, the so
called class 3 intermediate filaments, the class 4 intermediate filaments and
nerve cells and then the nuclear lamins class 5 intermediate filaments.
Intermediate filaments can be associated with a variety of different diseases. I'm
not going to ask you to remember these right now for an exam for our course,
this is just simple examples, there are hundreds of different examples of
intermediate filament protein mutations that are associated with diseases but
for example we already mentioned this epidermolysis bullosa is a mutation in
the genes that code for a keratin. Dilated cardiac myopathy, there's a
mutation in the vimentin gene. ALS or Lou Gehrig's disease, there's a mutation
in a desmin gene. Alzheimer's disease, there are abnormalities in glial
fibrillary acidic proteins, these accumulate in glial cells. Parkinson's
disease, there's a mutation in a neuro filament low molecular weight gene. A
mutation in a lamin B gene causes limb girdle muscular dystrophy
so again I put these up just to highlight for you that mutations in the
genes that code for intermediate filament proteins are clinically very
relevant and you'll encounter some of these in your training and pathology and
depending on your area of specialization you'll encounter these in your clinical
training later. Here are intermediate filaments that are visualized by light
and electron microscopy, the image on the left is from a lung fibroblast, vimenten
is stained red, actin microfilaments are stained in green and the nucleus
sustained with a stain called hoochst with just intercolates into the minor groove
of DNA. You don't have to remember that but you can see the
intermediate filaments scattered throughout the cell and you can see the actin
filaments in the cell. Here is an electron micrograph of an axon, you can
clearly see mitochondria, you can see microtubules at the arrowheads and the
little dots you can see as intermediate filaments like this so
these would be some of these so-called neuro filaments.