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Neuro Development and Disease > Protein Trafficking > Flashcards

Protein Trafficking Flashcards

1
Q

What can polarity be maintained by?

A
  • physical barrier (AIS)
  • selective trafficking
  • selective retention
  • selective degradation
  • local translation
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2
Q

What is localised translation?

A

when certain proteins are synthesised away from the cell body

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3
Q

When does the axon initial segment (AIS) form?

A

after axon establishment

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4
Q

What does the molecular sieve do?

A
  • prevent free diffusion of selected membrane and cytoplasmic proteins into axons
  • regulate the initiation of APs
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5
Q

What does the AIS have a similar molecular organisation to?

A

node of Ranvier

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6
Q

What is the key difference between the axon hillock and the AIS?

A

the axon hillock is present in the cell body of the neuron while the AIS is present in the proximal part of the axon

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7
Q

What is the role of the AIS in polarity maintenance?

A
  • serves as a submembrane diffusion barrier that restricts the mobility of plasma membrane components
  • acts as an intracellular selective filter for the transport of organelles and molecules through the cytoplasm
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8
Q

What is inter-compartmental transport essential for?

A

communication and support

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9
Q

Why are proteins and organelles in constant motion?

A
  • synapse formation (from sites of synthesis to sites of function)
  • for degradation
  • for everyday requirements
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10
Q

In axonal transport, where is the plus and minus end respectively?

A
  • minus = cell body
  • plus = extremities
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11
Q

What are kinesins?

A

plus end motors with 45 genes that take newly synthesised proteins from the cell out to the axon terminal

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12
Q

What is kinesin-13 and 14 respectively?

A
  • 13 = MT depolymerising (catastrophe promoting)
  • 14 = minus-end directed
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13
Q

What are the 3 major domains of a kinesin motor?

A
  • tail (cargo binding and auto inhibition mediation)
  • stalk (dimerisation domain)
  • head (motor domain)
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14
Q

What are the 6 steps of kinesin walking along an MT?

A
  1. in solution, both kinesin heads contain tightly bound ADP and move randomly
  2. when one of the heads (M2) encounters an MT, it binds tightly and releases ADP
  3. ATP rapidly enters the nucleotide binding site which triggers the neck linker to zipper onto the catalytic core
  4. this action throws the second head (M1) forward and brings it into contact with the next MT binding site
  5. the trailing head hydrolyses ATP, releasing phosphate
  6. the neck linker unzips from the trailing head and the leading head exchanges its nucleotide which allows it to zip to the catalytic core and the cycle repeats
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15
Q

How does the tail of kinesin bind the cargo?

A

via adapter proteins

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16
Q

Give an example of a cargo that binds directly to the tail domain without the need of adapter proteins

A

SNAP25

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17
Q

How can kinesin autoinhibition be relieved?

A

by cargo binding and phosphorylation mechanisms

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18
Q

How do autoinhibited kinesins work?

A

dual inhibitory mechanisms control kinesin-1, 2 and 3 motors through domains that inhibit MT binding and domains that inhibit processive motility

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19
Q

How can kinesin-1 motors be reactivated after autoinhibition by cargo binding?

A

the interaction with FEZ1 and JIP1 that releases the restraints of MT binding and processive motility

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20
Q

How can kinesin-7 motors be reactivated after autoinhibition by phosphorylation?

A

phosphorylation of the inhibitory tail domain by the kinases MPS1 and CDK1-cyclin B, which results in processive motility on MTs

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21
Q

What is the lifecycle of kinesin motors?

A
  1. in the absence of cargo, kinesin motors are autoinhibited
  2. during transport, motor-cargo complexes must navigate MT tracks
  3. at the destination, cargo release is coupled to inactivation of the motor
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22
Q

What is dynein?

A

a minus-end motor (only 1 motor, kinesin has 5)

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23
Q

What is dynein made up of?

A
  • 2 heavy chains
  • 2 intermediate chains
  • 2 light intermediate chains
  • 2 light chains
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24
Q

What are the 3 domains of each dynein HC?

A
  • head (motor) domain with ATPase activity
  • linker domain where MTs bind, and movement is generated
  • tail domain involved in dimerisation and cargo binding
25
Q

What are the intermediate chains in dynein?

A

a scaffold that links the HC with the LC and binds dynactin

26
Q

What do the light intermediate chains in dynein do?

A

bind adapter proteins (attached to HC)

27
Q

What are the light chains in dynein involved in?

A

the assembly of the dynein complex and cargo interactions

28
Q

What drives dynein motor action?

A

ATP hydrolysis

29
Q

What are the 5 steps of the dynein ATP hydrolysis cycle?

A
  1. ATP binds to site at AAA1and releases the motor from the MT
  2. remodelling of the linker to induce a bend and subsequent ATP hydrolysis
  3. the motor diffuses to a new site and rebinds
  4. the linker straightens during a power stroke to produce force which moves the whole dynein molecule forward and can induce tension between the 2 motor domains
  5. ADP release returns the motor to the beginning of the cycle (state 1)
30
Q

What do dynein adapters do?

A

regulate dynein motility

31
Q

What is dynactin?

A

an essential dynein adapter that is a complex of 23 proteins

32
Q

What are the functions of dynactin?

A
  • attaches cargoes to dynein
  • activates dynein motility
  • targets dynein to plus end of MT tracks
  • coordinates transport between dynein and kinesin motors
33
Q

What are the 3 main components involved in directing motors and cargoes to their destinations?

A
  • the AIS and motor targeting
  • motors exhibiting intrinsic directionality
  • cargo binding
34
Q

What can switching cargoes do to motors?

A

cause them to switch direction

35
Q

What is the new material to support during development?

A
  • axon and dendrite outgrowth
  • formation of synapses to form neuronal networks
36
Q

What is polarised trafficking required for in mature neurons?

A
  • addition of new proteins (synaptic plasticity)
  • degradation of faulty proteins
  • transport of signalling molecules from synapse to nucleus
37
Q

Why does transport deliver biomaterials for neurite growth?

A

there is a rapid expansion of size

38
Q

What is synaptogenesis?

A

formation of synapses

39
Q

What is synaptogenesis essential for?

A

polarity and function (neurotransmission)

40
Q

When do synapses form?

A

upon axon-dendrite contact

41
Q

What are the 3 steps of synaptogenesis?

A
  1. migration
  2. contact
  3. synapse formation
42
Q

What establishes and maintains synapses?

A

kinesin transport

43
Q

When are cargoes deposited?

A

when the axons and dendrites make contact i.e. when synapses form

44
Q

What are the 2 transport vesicles in axons?

A
  • synaptic vesicle precursor transport vesicles e.g. KIF1
  • piccolo-bassoon transport vesicles e.g. KIF5
45
Q

What is the main transport vesicle in dendrites and what do they do?

A

PSD95 containing vesicles that form postsynaptic densities

46
Q

What do the synaptic cell-adhesion molecules neurexins and neuroligins do?

A
  • connect pre- and postsynaptic neurons at synapses
  • mediate trans-synaptic signalling
  • shape neural network properties by specifying synaptic functions
47
Q

What does membrane fusion do?

A

deliver cargoes to their destination

48
Q

What happens after vesicles are released from cargo?

A

they undergo tethering

49
Q

What does dynein transport?

A

biomolecules back to the cell body for signalling and degradation

50
Q

What can problems with neuronal transport cause?

A

synapse loss and axon degeneration

51
Q

What can the APP family do?

A
  • both negatively and positively modulate main transmission systems
  • tune neuronal excitability by regulating intracellular calcium levels
52
Q

What can happen after focal blockages of axonal transport?

A

swelling then degeneration of the distal axon

53
Q

Give examples of axonal transport disruption and neurodegeneration

A
  • HD
  • AD
  • PD
54
Q

What does synaptic loss correlate to?

A

disease severity i.e. cognitive decline correlates to a decrease in the number of synapses in the brain

55
Q

What happens in prodromal AD?

A
  • circuit disruption
  • mild synapse loss
  • amyloid fibril forms on excitatory neuron
56
Q

What happens in late-stage AD?

A
  • hyper excitability
  • inflammation
  • synapse loss
  • loss of inhibitory tone
  • deficits in autophagy
57
Q

What is a classic protein affected by reduced levels of motor proteins in AD patients?

A

synaptophysin

58
Q

What are Aβ oligomers?

A

highly neurotoxic oligomers that can further aggregate to form soluble protofibrils (large oligomers) and then insoluble β-pleated sheets forming amyloid fibrils and plaque

59
Q

What are the 7 stages leading to neurodegeneration?

A
  1. initiating factors e.g. ageing, lifestyle, toxins
  2. pathological proteins e.g. abnormal tau, Aβ oligomers
  3. aberrant kinase and phosphatase activity e.g. PP1, GSK
  4. impaired fast axonal transport
  5. synaptic dysfunction and axonal degeneration
  6. functional impairment e.g. memory loss, cognitive defects
  7. neurodegeneration

Neuro Development and Disease (9 decks)

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