Cytoskeletal Abnormalities

8/12/2019 Cytoskeletal Abnormalities

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CYTOSKELETAL

AND ABNORMALITIES



OUTLINE

Definition

Functions of cytoskeleton

Structure of cytoskeleton

Cytoskeletal abnormalities Summary



DEFINITION Cytoskeleton is a network of fibres throughout the

cell’s cytoplasm that help’s the cell maintain itsshape and gives support to the cell.

Composed of 3 protein filaments

1. Microfilaments2. Microtubules

3. Intermediate filaments





FUNCTIONS OF CYTOSKELETON

Maintains cell shape.

Protects the cell from wear & tear mechanism.

Provides mechanical strength to cell.

Enables cellular motion.(cilia&flagella)

Helps in chromosome separation in mitosis &meiosis i.e.cellular division.

Intracellular transport of organelles.

Helps in muscle fibre contraction.



STRUCTURE OF CYTOSKELETON

MICROFILAMENTS: Solid rod like structures measuring

6nm in diameter.

Composed of mostly ACTIN.

Seen as two intertwined chains.

Two forms G actin & F actin.

Two ends plus end & minus end.

Actin with MYOSIN helps in musclecontraction & movement.



How Actin concentration is maintained in

body?

G actin binding protein called PROFILIN is an

actin binding protein.

Actin+profilin certain stimuli

Cannot assemble profilin releases

bound actin

So reduces free actin conc increases

MF formation seen

actin concentration.



FUNCTIONS OF MICROFILAMENTS

Mostly concentrated just below cell membrane.

Resists tension of cell & maintains cellular shape.

Anchors membrane proteins.

Cytoplasmic protruberances pseudopodia &microvilli.

Muscle contraction.

Cytoplasmic streaming in most cells. Participates in cell-to-cell & cell-to-matrix

junctions.



MICROTUBULES

A MT is a polymer of globular tubulin subunits which are

arranged in a cylindrical tube measuring 24nm in diam

Polymers of alpha & beta tubulins.

1 MT formed by 13 protofilaments.

MT’s nothing but cylinders of longitudinally oriented

protofilaments.





Singlet protofilament.

Doublet

protofilament.ex:cilia,flage

lla. Triplet

protofilament.ex:basal

bodies,centrioles.





MT STABILITY AND INSTABILITY

Two ends:

Alpha subunit (or) – ve endcappedno elongation.

Beta subunit (or) +ve endelongation seen.

Alpha GTP & beta GTP.alpha GTP stableno disassembly seen.

beta GTP unstableGDPdisassembly seenshrinkage ofMTif alpha GTP added shrinkage stops.





MAP’S(MT ASSOCIATED PROTEINS)

They stabilizes MT’s by binding to outer surface of MT

protofilaments.

MAP phosphorylation by MARK MAP detach from

MTMT falls apart. Type 1:MAP1a,MAP1baxons,dendrites.

Type 2:MAP2,MAP4,TAUdendrites,axons.





INTERMEDIATE FILAMENTS

These are 10-15nm in diam.

Formationmonomer,dimer,tetramer.

Anti-parallel orientation of tetramers seen.so no polarity

seen.+ve or – ve ends.

Assembly & disassembly is regulated by cycles of

phosphorylation & dephosphorylation.







Type 3:

Four proteins are present.

Desmincomponent of sarcomere in muscle cell.

GFAPastroglial cells.

Peripherin

peripheral neurons. Vimentinmost widely distributed.Found in

fibroblasts,leukocytes,blood vessel endothelial cells.



Type 4: Neurofilaments L,M,Haxons of neurons.

Alpha internexin.

Synenin.

Syncoilin.



Type 5: Nuclear laminsLMNA,LMNB1,LMNB2.

Type 6:

Nestinfound in embryonic neurons.



CYTOSKELETAL ABNORMALITIES

Microfilaments:

Wiskott-Aldrich syndrome.

Congenital myopathies.

nemaline myopathy

myotubular myopathy

central core myopathies

congenital fiber typedisproportion



WISKOTT-ALDRICH SYNDROME

WASP(wiskott aldrich syndrome protein)

Expressed in WBC & megakaryocytes& involved inreorganization of actin cytoskeleton.

WASP is essential for function of T cells & platelets. Pt’s with WAS has defective gene in short arm of X

chromosome(Xp11.23)

Defective gene encodes protein WASP



Continued…………

Causes mutations in WASP.

So inhibits actin reorganization. CD3 cannot be presented,T cells not activated,so B

cells not activated,only IgM Ab’s are produced.

So no cell growth & division(proliferation) seen.

These defective cells also have problems with cell

motility,difficulty attaching to other cells.



Continued……….

Pt presents aseczema,recurrentinfections,microthrombocytopaenia,nose

bleeds,bloodydiarrhea,auto immunedisorders etc.

It is a X linked recessive

genetic trait.



NEMALINE MYOPATHY

Also called rod myopathy or nemaline rod myopathy.

Congenital hereditary neuromuscular disorder.

6 genes are imp that provide instructions for producing

proteins in muscle sarcomeres that are necessary for

muscle contraction.



Continued……….

6 genes are:

ACTA1-alpha actin 1 gene.

TPM3-alpha tropomyosin.

NEB-nebulin gene.

TPM2-tropomyosin2.TNNT1-troponin T1.

CFL2-coffilin2 gene.

In NM, mutations in all these 6 genes are seen.



Continued……….

So the proteins are disorganized,can’t interact normally

& disrupts the muscle contraction. Muscle weakness is the prominent feature in these pt’s.

When skeletal muscles of these pt’s are stained &

viewed under microscope,they show rod like structures

called NEMALINE BODIES.







Continued……….

Nemaline bodiesare abnormal thread like rods derived

from Z band of sarcomere,spindle shaped,measuring 1-7microm in length,0.3-2microm in width.Produced due

to mutations in alpha actin gene leading to marked

sarcomere disorganization.

Pt presents as muscle weakness

arms,legs,trunk,throat,face muscles,delayed motor

development also seen.





MICROTUBULES

MAP’S pathology

TAUOPATHIES: These are class of neurodegenerative disorders resulting

from pathological aggregation of TAU protein in brainneurons & glial cells.

Ex’s:Alzheimer’s disease

Pick’s disease

Frontotemporal dementia

Progressive SN palsy

Corticobasal degeneration



Alzheimer’s disease

Hyperphosphorylation of tau protein due to

mutation is the main pathology in all disorders.

So disrupts normal structure & function of

neuroglial cells.

It is common cause of dementia in elderly. GROSSLY:varied degrees of cortical atrophy

seen,widening of cerebral sulci mostly in

frototemporalparietal lobes seen.Compensatory

ventricular enlargement also seen.





Continued………

HP diagnostic features are:

Neuritic plaques Neurofibrillary tangles.

NP’Sare focal spherical collections ofdark,irregular,thread like structures.Central core is

represented by beta amyloid.Irregular beaded linearstructures represent abnormal dendrites,axons withdegenerative changes.

NFT’STwisted remnants of tau protein.Appear aselongated flame shaped in pyramidal neurons.





PICK’S DISEASE

Tau protein mutations seen.

Presents as progressive dementia.

Mostly frontotemporal lobes affected.

So alteration in personality(frontal lobe signs) & language

disturbances(temporal lobe signs) seen. GROSSLY:frontotemporal lobes atrophy seen.sometimes

atrophy will be very severe with knife like gyri.





Continued……..

HP:

Neuronal loss most severe in outer 3 layers of cortex. Surviving neurons show characteristic swelling called

Pick cells.

Others contain PICK BODIES composed of numerous tau

fibrils arranged in disorderly manner,which arecytoplasmic round to oval filamentous inclusions.Stainstrongly with silver stain.





FRONTO TEMPORAL DEMENTIA

Mutations in MAPT encoding tau protein seen. GROSSLY:Atrophy of frontotemporal lobe of varying

degree seen.

Atrophic regions of cortex marked by neuronal

loss,gliosis,presence of tau containing neurofibrillary

tangles.





CILIA DYSFUNCTION SYNDROME

Cilia linesupper&lower r.t.,sinuses,E.T.& F.T. &

middle ear. Cilia & flagellainner & outer dynein arms.

Dynein armsATPasesliding & cilia bending.

Mutations in DNAI1,DNAH5code for proteins in

dynein.

Absence or shortening of dynein arms.

Lung secretions can’t be clearedreurrent infections.







INTERMEDIATE FILAMENTS

89 diseases have been associated with IF’S.

TYPE 1&2 DISORDERS:

Epidermolysis bullosa simplex disease.

Keratoderma disorderskeratin mutations.

Hair & nail defects. Keratin disorders affecting other tissues.

Other systems involvement.



EPIDERMOLYSIS BULLOSA

Heritable skin blistering disorder. Mutations in keratins K 5/14 seen.

So fragility of basal layers of epidermis/dermis.

Breakage seen.Epidermis comes away from connective

tissue blister forms.

E/M:split in epidermis seen.





KERATODERMA DISORDERS

Autosomal dominant condition. K 1/10 mutations seen.

Patient presents with redness,blistering,hypertrophy of

skin(ichtyosis).

HP:suprabasal cell layers of epidermis are ruptured.

EM:keratin filament bundles are clumped,giving

appearance of dense perinuclear shell.





PACHYONYCHIA CONGENITA:

Type 1 & 2 present.

Mutations in K 6/16/17 seen. Hypertrophic nail dystrophy is prominent feature.

Thickened nails in foot soles is mostly seen.

MONILETHRIX:

Autosomal dominant disorder.

Mutations in K 81 & 86(trichocytic keratin) seen.

Varying degree of hair loss seen.F/H present.

Affected hairsfracturing,weathering,splitting,brittleness

seen. U/S analysis show defect in structure of hair shaft.





WHITE SPONGE NEVUS OF CANNON:

Oral leukokeratosis seen.

Mutations in K 4 & 13 seen.

So non cornifying stratified squamous epithelium is

affected.

Fragility in suprabasal cells of buccal epithelium seen. Pt presents as white plaques & patches of loose skin in

mouth & cheek.

Anal & genital epithelium also affected.



MEESMANN CORNEAL



MEESMANN CORNEAL

DYSTROPHY

K 3/12 mutations seen. E/M:cytoplasmic inclusions & keratin aggregates seen

within corneal keratinocytes.

Pt presents with photophobia,contact lens

intolerance,reduction of visual acuity.IBD,LIVER & PANCREATIC DISEASES:K 8 & 18

mutations seen





TYPE 3 DISORDERS

DESMIN:structure,mechanical integrity of cell

during muscle contraction maintained.Present inskeletal,smooth,cardiac muscle.

Desmin Related Myopathies:

Mutations in desmin seen.

Desmin protein accumulates in muscle fibre.Contraction lost. So weakness in skeletal,smooth,cardiac muscles seen.

EX’S:Distal myopathy.

dilated CMP with conduction system defects.

familial restrictive CMP.limb girdle muscular dystrophy



PERIPHERIN:Present in nerve cells of brain & spinalcord.

Transmits impulses,connects brain & SC to muscles& controls their movement.

Amyotrophic Lateral Sclerosis:

Peripherin mutations seen. 3 dimentional shape of it is lost.Forms clumps ^&

aggregates within nerve cells.

Disrupts normal nerve function.

Death of motor neurons seen. Loss of motor neurons in brain,brain stem,spinal cord

seen.ultimately leading to paralysis.



GFAP:Gives strength & support to neuroglialcells(myelin sheath,transmission,bl-br barrier)

Alexander Disease:

GFAP mutations seen.

Neurodegenerative disorder.

Dementia,seizures,spasticity,developmental defectsseen.

VIMENTIN:BFSP2 vimentin mutations seen.

Autosomal Dominant Juvenile Cataract:

Lens clear at birth. Develop opacities in 2nd or 3rd decades of life.



TYPE 4 DISORDERS



TYPE 4 DISORDERS

NEUROFILAMENTS:

Helps in axonal growth,controls axonal diameter. Also controls how fast electrical impulses travel down the

axon.

CMTD TYPE2 & TYPE1:

Progressive neuro degenerative conditions.

Mutations in NF gene seen.

Repetitive demyelinationn & remyelination seen.

Cavus deformity common in most patients.

Amyotrophic Lateral Sclerosis:

NF-H & peripherin both mutations are seen.





Parkinson’s Disease:

NF-L & NF-M mutations seen. Degenerative disorder of CNS.

Motor skills,speech affected.

Pt presents with muscle rigidity,tremors,postural &

gait abnormalities,bradykinesia,akinesia,dementia

etc..

Lewy bodiesalpha synuclein depositions in

neuronal body.Seen as round,lamellated,eosinophiliccytoplasmic inclusions/protein accumulations.



TYPE 5 DISORDERS



TYPE 5 DISORDERS

LAMINOPATHIES:

This is the term used for diseases caused by mutations inlamin genes-LMNA,LMNB1,LMNB2,LMNC1.

Lamin genes:Involved in nuclear stability,chromatin

structure,gene expression,interacts with integral proteins

of inner nuclear membrane.

Mutationsdisrupts cellular structure & function.

Lipodystrophy Disorders



podyst op y so de s

Familial Partial Lipodystrophy:

LMNA gene mutations.

Fat loss(limbs,thorax,abd,face).

Abnormal accumulation(buffalo hump).

Type 2 diabetes.

Acquired Partial Lipodystrophy:

LMNB2 gene mutations.

Fat loss(NOT from lower extremities).

F/H absent.

Generalised Lipodystrophy Syndrome: Rare one.insulin resistant diabetes

seen.CMP,thickening,calcification of valves,liversteatosis seen.



Muscle Laminopathies



Muscle Laminopathies

Emery-Dreifuss Muscular Dystrophy:

Autosomal dominant & recessive present. LMNA gene mutations.Skeletal,cardiac muscles

involved.

So muscle wasting,tendon

contracture,CMP,conduction defects are seen.Limb Girdle Muscular Dystrophy:

LMNA gene mutations seen.

Distinguished from above by absence of rigid

spine,contracture,occasionally calf hypertrophy seen.



Dilated CMP & Conduction Defects:

LMNA,LMNC1 mutations seen.

Ventricular dilatation,reduced systolicfunction,heart failure.

Sinus bradycardia,AV conduction block,atrialarrythmias seen.

Congenital Muscular Dystrophy:

LMNA mutations seen.

Autosomal recessively inherited disorder.

Hypotonia,muscle weakness,contracture seenat birth/6 months.

Physical dysability,motor development

delay,sr.CK elevation,brain defects seen.

Neurological Disorders



Neurological Disorders

Charcot Marie Tooth Disease type 1& 2

Axonal Neuropathy.

Autosomal Dominant Spinal Muscular Dystrophy(ant

horn cells degeneration) Autosomal Dominant Leukodystrophy(myelin loss)



Premature Ageing Syndromes

Atypical Werner Syndrome: LMNA mutations seen.

Premature ageing,short stature,bird like faces,hoarsevoice,premature greying,thinning hair,early onset cataractsetc…seen.

Hutchinson-Gilford Progeria Syndrome: Healthy at birth.C/F’s seen in 1st few yrs of life.

Growth retardation,incomplete sexual maturation,low wt forht ratio,atherosclerosis,loss of subcutaneous fat,skinwrinkling,alopecia,craniofascial alterations seen.Mental &emotional development is normal.Die between 7-27 yrs fromcardiovascular diseases.





TYPE 6 DISORDERS

Autosomal Dominant

Cataract

Autosomal Recessive

Cataract

SUMMARY



SUMMARY

Cytoskeleton maintains cell shape & gives support

to cell. 3types:Microfilaments,Microtubules,Intermediate

filaments(6 subtypes).

Microfilaments disorders:

Wiskott-aldrich syndrome. Congenital myopathies.

Microtubule disorders:

Tauopathies

1. Alzheimer’s disease. 2. Pick’s disease.

3. Progressive supranuclear palsy.

4. Corticobasal degeneration.

SUMMARY



SUMMARY

Cilia dysfunction syndrome

1. Immotile cilia syndrome

2. Kartageners syndrome

3. Infertility syndrome

Intermediate filaments disorders:

Type 1&2 disorders

1. Epidermolysis bullosa2. Keratoderma disorders

3. Hair & nail disorders

4. Other systems involvement

Type 3 disorders1. Desminopathies(desmin)

2. Amyotropic lateral sclerosis(peripherin)

3. Alexander disease(GFAP)

4. Autosomal dominant juvenile cataract(vimentin)

SUMMARY



SUMMARY

Type 4 disorders:(neurofilament)

1. Charcot-marie-tooth disease2. Parkinson’s disease

Type 5 disorders:(nuclear lamins)

1. Lipodystrophy disorders2. Muscular laminopathies

3. Neurological disorders

4.Premature ageing syndrome

Type 6 disorders:(nestin)

1. Autosomal dominant cataract

2. Autosomal recessive cataract



REFERENCES

Robbins & cotron textbook of pathology-8th

edition. Anderson textbook of pathology.

Internet.



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Cytoskeletal Abnormalities