CYTOSKELETAL AND ABNORMALITIES

OUTLINE
Definition

Functions of cytoskeleton
Structure of cytoskeleton Cytoskeletal abnormalities Summary

DEFINITION

Cytoskeleton is a network of fibres throughout the cells cytoplasm that helps the cell maintain its shape and gives support to the cell. Composed of 3 protein filaments
1. 2. 3.

Microfilaments Microtubules 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 formsG actin & F actin. Two endsplus end & minus end.

Actin with MYOSIN helps in muscle

contraction & 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 actin conc increases MF formation seen

So reduces free

actin concentration.

FUNCTIONS OF MICROFILAMENTS
Mostly concentrated just below cell membrane.
Resists tension of cell & maintains cellular shape. Anchors membrane proteins. Cytoplasmic protruberancespseudopodia &

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. MTs 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 Beta subunit (or) +ve endelongation seen. Alpha GTP & beta GTP.

elongation.

alpha GTP stableno disassembly seen. beta GTP unstableGDPdisassembly seenshrinkage of MTif alpha GTP added shrinkage stops.

MAPS(MT ASSOCIATED PROTEINS)

They stabilizes MTs by binding to outer surface of MT

protofilaments. MAP phosphorylation by MARKMAP detach from MTMT falls apart. Type 1:MAP1a,MAP1baxons,dendrites. Type 2:MAP2,MAP4,TAUdendrites,axons.

FUNCTIONS OF MICROTUBULES
Involved in: Mitosis(formation of mitotic spindle). Cytokinesis. Vesicular transport. Extension of neuronal growth cone. Beating of cilia & flagella.

INTERMEDIATE FILAMENTS
These are 10-15nm in diam. Formation monomer,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.

TYPES OF INTERMEDIATE FILAMENTS

6types based on similarities in amino acid sequence and

protein structure. Type 1&2:ACIDIC AND BASIC KERATINS Mechanically stabilizes cell against physical stress. Epithelial keratinsbladder,skin etc. Trichocytic keratinhair,nail,horns,reptilian scales etc.

Type 3: Four proteins are present. Desmin component of sarcomere in muscle cell. GFAPastroglial cells. Peripherinperipheral 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: Nestin found in embryonic neurons.

CYTOSKELETAL ABNORMALITIES
Microfilaments: Wiskott-Aldrich syndrome. Congenital myopathies. nemaline myopathy myotubular myopathy central core myopathies congenital fiber type disproportion

WISKOTT-ALDRICH SYNDROME
WASP(wiskott aldrich syndrome protein)
Expressed in WBC & megakaryocytes& involved in

reorganization of actin cytoskeleton. WASP is essential for function of T cells & platelets. Pts 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 Abs 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 as

eczema,recurrent infections,microthrombocy topaenia,nose bleeds,bloody diarrhea,auto immune disorders 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,cant interact normally

& disrupts the muscle contraction. Muscle weakness is the prominent feature in these pts. When skeletal muscles of these pts 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 17microm 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
MAPS pathologyTAUOPATHIES: These are class of neurodegenerative disorders resulting

from pathological aggregation of TAU protein in brain neurons & glial cells. Exs:Alzheimers disease Picks disease Frontotemporal dementia Progressive SN palsy Corticobasal degeneration

Alzheimers 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. NPSare focal spherical collections of dark,irregular,thread like structures.Central core is represented by beta amyloid.Irregular beaded linear structures represent abnormal dendrites,axons with degenerative changes.

NFTSTwisted remnants of tau protein.Appear as elongated flame shaped in pyramidal neurons.

PICKS 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 are cytoplasmic round to oval filamentous inclusions.Stain strongly 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.

CorticoBasalDegeneration: Same MAPT halotype mutations involved. Tau positive threads in grey & white matter are specific for diagnosis. Progressive SupraNuclearPalsy: MAPT halotypes involved. Neuronal loss seen in globus pallidus,substantia nigra,colliculi,dentate nucleus of cerebellum,subthalamic nucleus. NFTS seen in affected regions,neurons,glia.

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 cant be clearedreurrent infections.

Continued.
IMMOTILE CILIA SYNDROME: Autosomal recessive disorder. Recurrent infections,sinusitis,bronchitis,pneumonia,otitis media are seen. KARTAGENERS SYNDROME: Chronic sinusitis,bronchiectasis,situs inversus(reversal of internal organs) INFERTILITY: Defective cilia function in F.T.female infertility. Defective flagella functionsperm motility affectedmale infertility.

INTERMEDIATE FILAMENTS
89 diseases have been associated with IFS.

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

tissueblister 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 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 in skeletal,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. EXS:Distal myopathy. dilated CMP with conduction system defects. familial restrictive CMP. limb girdle muscular dystrophy

PERIPHERIN:Present in nerve cells of brain & spinal cord. 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 neuroglial cells(myelin sheath,transmission,bl-br barrier) Alexander Disease: GFAP mutations seen. Neurodegenerative disorder. Dementia,seizures,spasticity,developmental defects seen. 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
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.

Parkinsons 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,eosinophilic cytoplasmic inclusions/protein accumulations.

TYPE 5 DISORDERS
LAMINOPATHIES: This is the term used for diseases caused by mutations in lamin 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
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,liver steatosis seen.

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 systolic function,heart failure. Sinus bradycardia,AV conduction block,atrial arrythmias seen. Congenital Muscular Dystrophy: LMNA mutations seen. Autosomal recessively inherited disorder. Hypotonia,muscle weakness,contracture seen at birth/6 months. Physical dysability,motor development delay,sr.CK elevation,brain defects seen.

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,hoarse

voice,premature greying,thinning hair,early onset cataracts etcseen.

Hutchinson-Gilford Progeria Syndrome:

Healthy at birth.C/Fs seen in 1st few yrs of life. Growth retardation,incomplete sexual maturation,low wt for

ht ratio,atherosclerosis,loss of subcutaneous fat,skin wrinkling,alopecia,craniofascial alterations seen.Mental & emotional development is normal.Die between 7-27 yrs from cardiovascular diseases.

TYPE 6 DISORDERS
Autosomal Dominant

Cataract Autosomal Recessive Cataract

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. Alzheimers disease. 2. Picks disease. 3. Progressive supranuclear palsy. 4. Corticobasal degeneration.

SUMMARY
1. 2. 3.

Cilia dysfunction syndrome Immotile cilia syndrome Kartageners syndrome Infertility syndrome Intermediate filaments disorders: Type 1&2 disorders 1. Epidermolysis bullosa 2. Keratoderma disorders 3. Hair & nail disorders 4. Other systems involvement Type 3 disorders 1. Desminopathies(desmin) 2. Amyotropic lateral sclerosis(peripherin) 3. Alexander disease(GFAP) 4. Autosomal dominant juvenile cataract(vimentin)

SUMMARY
Type 4 disorders:(neurofilament) 1. Charcot-marie-tooth disease 2. Parkinsons disease Type 5 disorders:(nuclear lamins) 1. Lipodystrophy disorders 2. 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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