Cytoskeleton

Question 1

three major cytoskeletal components

Answer 1

microtubules, microfilaments, and intermediate filaments

Question 2

key points on microtubules

Answer 2

• thickest cytoskeletal component
• found in the cytoplasm of all cells
• radiate from the centrosome, or MTOC
• MTOC regulates their growth
• form tubulin protein

Question 3

key points on microfilaments

Answer 3

• thinnest cytoskeletal component
• support and maintain cell shape
• adhere to ec matrix and to other cells
• form actin/myosin proteins

Question 4

key points on intermediate filaments

Answer 4

• strengthen the cellular cytoskeleton
• form different proteins in different cells!

Question 5

what proteins do intermediate filaments form in epithelial, mesenchymal, muscle, glia, and nerve cells?

Answer 5

epithelial: keratin
mesenchymal: vimentin
muscle: desmin
glia: glial fibrillary acidic protein
nerve: neurofilaments
presence of these proteins can be a diagnostic marker of what type of cell a tumor originated from!

Question 6

what types of proteins are essential for cytoskeletal function?

Answer 6

• accessory proteins!
• various ones are in different tissues

Question 7

list some actin-binding proteins (accessory proteins) in microfilaments

Answer 7

anchoring proteins: ankyrin, spectrin, dystrophin
cross-linking proteins: actinin, filamin

Question 8

examples of defective anchoring proteins in microfilaments

Answer 8

• defective ankyrin and/or spectrin can affect the membrane cytoskeleton of rbc’s, causing them to become spherical instead of biconcave (normal)
• these are called spherocytes: these are less able to move around and also have increased permeability to Na due to defective Na/K ATPase
• ultimately, these issues cause them to be phagocytosed, resulting in decreased rbc lifespan and low blood levels
• names: spherocytosis (spherocyte presence) and elliptocytosis (elliptocyte presence)
• these are autosomal dominant disorders

Question 9

what is an example of abnormal assembly of intermediate filaments in epithelial tissues?

Answer 9

mutant keratin genes (keratin is the protein made by intermediate filaments in epithelial cells) cause skin diseases

Question 10

list the three skin diseases we talked about, the type of keratin they affect, and the affected layer of the epidermis

Answer 10

1. epidermolytic plantopalmar keratoderma (EPPK) - keratin 9 (plantopalmar epidermis) - stratum corneum
2. epidermolytic hyperkeratosis (EH) - keratins 1 and 10 - stratum granulosum and spinosum
3. epidermolysis bullosa simplex (EBS) - keratins 5 and 14 - stratum basale

Question 11

describe the overall manifestation of mutant keratin genes

Answer 11

expression of mutant keratin genes results in abnormal assembly of intermediate filaments in epithelial cells, which weakens mechanical strength of cells, ultimately causing inherited skin diseases

Question 12

where are microtubules found and how are they organized?

Answer 12

• found in the cytoplasm of all cells, radiating from centrosome or MTOC
• organized into specialized structures:
  
  • mitotic spindle and centrioles: found in most cells
  • cilia, flagella, and basal bodies: more limited distribution

Question 13

types of MAPs

Answer 13

• assembly MAPs: regulate dynamic turnover of microtubules by cross-linking them to each other, promoting polymerization, or inhibiting depolymerization
• motor MAPs: (kinesins and dyneins) use energy to walk or slide along microtubules, usually carrying vesicles

Question 14

what do PC1 and PC2 ultimately do?

Answer 14

regulate normal kidney function - mutations of these channels result in autosomal dominant polycystic kidney disease (ADPKD)

Question 15

describe normal function of PC1

Answer 15

• large, multifunctional transmembrane protein that serves as a sensor
• most active in kidney cells before birth
• much less of this protein is made in normal adult kidneys
• found in primary cilia, which are found in nephrons

Question 16

pathogenesis of ADPKD

Answer 16

1. epithelial cells with loss-of-function of PC1 or PC2 show higher rates of proliferation/apoptosis and reduced autophagy (this is caused by decreased Ca2+ signaling?)
2. Ca2+ signaling disruption leads to increased apoptosis and proliferation, autophagy inhibition
3. ultinately the renal cyst-lining epithelial cells are converted to a secretory phenotype instead of functioning as absorptive cells, and they have higher rates of proliferation and apoptosis

Question 17

what is PC2?

Answer 17

• a Ca2+ permeable cation channel that works alongside PC1

Question 18

what genes code for PC1 and PC2?

Answer 18

• PKD1 and PKD2 (THESE ARE ABNORMAL GENES THE PRODUCE ABNORMAL PROTEINS), which adversely affect renal tube development
• PKD1 is on chromosome 16
• PKD2 is on chromosome 4

Question 19

which type of PKD is the most prevalent?

Answer 19

• ADPKD is actually the most prevalent genetic disorder, involves dysfunctional primary cilia leading to cyst formation and ultimately renal failure
• note: PKD affects men and women of all races, and causes nearly 10% of all end-stage renal disease

Question 20

what are cysts and what is their formation tied to in PKD?

Answer 20

• cysts are non-functioning tubules filled with fluid pumped into them (see absorptive epithelium to secretory epithelium)
• cyst formation is tied to abnormal primary cilia-mediated signaling, predominantly impaired Ca2+ entry and proliferative cell pathway (PC1 and PC2 dysfunction)

Question 21

structural difference between motile and non-motile cilia

Answer 21

non-motile: 9 doublet microtubules
motile: 9 doublet microtubules and 2 singlet microtubules in the center

Question 22

describe the structure of motile cilia

Answer 22

• 9 doublet microtubules connected by nexin links
• tektin proteins run up alongside the microtubules
• inner and outer dynein arm attached to the A microtubule of each doublet
• 2 singlet microtubules in the center

Question 23

describe the mechanism by which motile cilia move

Answer 23

• axonemal dynein binds the dynein arms, causing the microtubules to slide alongside each other
• this sliding force is towards the (-) end of the neighboring doublet, giving each section of the axoneme a distinct polarity and clock-wise orientation

Question 24

what is kartagener’s syndrome?

Answer 24

• known as immotile cilia syndrome
• results from structural abnormalities in the axoneme, specifically defective or absent dynein
• this prevents mucociliary clearance in airways, leading to persistent lung infections and bronchiectasis (dilation of bronchi and bronchioles)
• also reduces sperm motility and egg transport in the oviduct, possible sterility
• because cilia play a role in directing tissue development during embryonic development, there is a 50% change of situs inversitus in these individuals
• autosomal recessive disorder

Question 25

describe how microtubules can be used as anti-mitotic drug targets

Answer 25

• tubulin (made of microtubules) and chromatin make up the mitotic spindle, a cytoskeletal component that is essential during cell division
• microtubules assemble and disassemble (dynamic instability) to form spindles that assemble/disassemble during mitosis
• microtubule targeted drugs can inhibit polymerization (microtubule-destabilizing) or inhibit depolymerization (microtubule-stabilizing)
• this stops cells in metaphase of mitosis, stopping proliferation