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Tissue Pathology > Nerve > Flashcards

Nerve Flashcards

1
Q

Define retrograde movement

A

Movement of old components no endocytosis molecules from synapse to cell body for degradation/recycling

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2
Q

Anterograde Movement

A

Movement of molecules and protein in transport vesicles from cell body along axon

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3
Q

Features of Dyneins

A

Retrograde transport
>1,000,000kDa
Tail = cargo binding region
Motor unit consisting of:
Associated ATPase head
MTBD stalk
Globular heads bind dyne in to MT facilitated by MTBD
Requires association with dynactin acting as a co-factor to transport cargo

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4
Q

The dynactin complex consists of at least __ subnets.

A

8

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5
Q

List two important subunits of dynactin

A
  1. A short actin-related protein (Arq1) that binds dynamitin essential for cargo binding
  2. P150glued - a protein that binds MT
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6
Q

Kinesins can be…

A

…monomers, homodimers, heterodimers…

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7
Q

What are the two most important sites within a motor protein?

A

Motor and Tail

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8
Q

Kinesin motor protein features

A

Motor domain:
Beta sheet sandwiched between 2x alpha helices
Functions include microtubules binding, ATP binding, and ATP hydrolysis

Tail domain:
Binds cargo through transmembrane receptors

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9
Q

Motor protein walking

A

ATP head of MT binding domain binds Beta-tubulin
Release ATP
Trailing ADP end swings around in front of leading head
Binds new beta tubulin
ATP trailing head releases a phosphate to become ADP and unbinds the beta tubulin

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10
Q

Define proteostasis

A

Balancing of cellular pathways that are responsible for protein synthesis, folding, processing, assembly, trafficking, localisation and degradation.

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11
Q

What are the potential fates of newly synthesised proteins?

A

Chaperoned to either the ubiquities proteosome system or the autophagy lysosome pathway

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12
Q

What is ubiquitin?

A

A 76 amino acid protein that can be covalently linked to lysine residues of proteins targeted for Intracellular degradation by proteasomes.

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13
Q

What are proteasomes?

A

Multimeric proteases with a barrel shaped core and a cap that recognises polyubiquitinated proteins

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14
Q

Protein(s) associated with Parkinson’s disease

A

Alpha synuclein

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15
Q

Protein(s) associated with Alzheimer’s disease

A

Amyloid beta and Tau

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16
Q

Protein(s) associated with Multiple Taupathies

A

Tau (MT ass.)

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17
Q

Protein(s) associated with Huntington’s Disease

A

Huntingtin with tandem glutamine repeats

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18
Q

Features of Alzheimer’s disease

A

Degeneration of neurons, particularly in basal forebrain and hippocampus
Synaptic pathology and altered neuronal connections

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19
Q

Features of beta amyloid

A

Derived from proteolytic processing of amyloid precursor protein
Peptides come together to form amyloid fibrils with filamentous structure
2 kinds AB40 and AB42

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20
Q

Beta Amyloid Functions

A

Antimicrobial activity
Tumour suppression
Sealing leaks in blood brain barrier (BBB)
Promoting recovery from brain injury

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21
Q

List the Antimicrobial activity of amyloid beta

A

Antibacterial, antifungal and antiviral properties effective against at least 11 species of microbe

22
Q

Describe the Antimicrobial nature of beta amyloid

A

Antibacterial, antifungal, and antiviral properties effective against at least 11 different microbe species

23
Q

Describe the tumour suppressive nature of beta amyloid

A

Beta amyloid may intercept oncogenes viruses and suppress tumour growth

24
Q

How does amyloid beta seal leaks in the BBB?

A

AB binds blood-borne solutes together to form a plug that prevents the spread of neuro active and toxic components into the brain

25
Q

The presence of ____________ results in better outcomes in recovery from brain injury in animal models.

A

Beta Amyloid

26
Q

What are the extracellular protein aggregates in AD?

A

AB plaques

(Neurotic plaques and extracellular lesions)

27
Q

What are the intracellular protein aggregates in AD?

A

Neurofibrillary tangles

(MAPs -> NFTs)

28
Q

5 stages in the formation of a B-Amyloid Plaque

A

1️⃣ APP spans the cell membrane
2️⃣ B-Secretase cleaves APP
3️⃣ Y-secretase cleaves the remaining membrane- bound portion
4️⃣ Amyloid-B is released from the cell (the length of the peptide reflects the site at which y-Secretase makes its cut)
5️⃣ All forms of amyloid-B aggregate into oligomers => fibrils => plaques

29
Q

Features of Tau

A

Normally, a MAP involved in MT stabilisation
Highly soluble
Expressed throughout the CNS and PNS
Primarily found in axons where it regulates polymerisation and stabilisation

30
Q

Describe the two mechanisms that allow tau to control MT

A
  1. Kinase mediated phosphorylation - detaches tau from MT
  2. Dephosphorylation reaction by phosphates - restores MT binding ability
31
Q

Name an indirect meachanism of tau hyperphosphorylation

A

Oxidative stress

32
Q

List two direct mechanisms of tau hyperphosphorylation

A

Mutations
Down-regulation of phosphatases

33
Q

Explain the mechanisms that lead to a loss of function due to hyperphosphorylation

A

MT detachment
Loss of stabilising function
Change in dynamics

(This is a cycle of events)

34
Q

Explain the mechanisms that lead to a toxic gain of function of hyperphosphorylated tau

A

NFTs made up of hyperphosphprylated tau sequester normal tau
NFTs become physical obstacles to the transport of vesicles and other cargos

35
Q

Tau aggregation has _______ implications than __________ due to its Intracellular effect.

A

Greater
Beta Amyloid plaques

36
Q

What does changes in MT dynamics lead to?

A

Compromised axonal transport (neurotoxicity)

37
Q

Methods to target tau therapeutically

A

Small molecule MT stabilising agents may compensate for reduction in tau interaction with MT
Inhibitors of tau kinases may improve MT function

38
Q

Explain the difficulties of degrading tau enzymatically and potential methods to overcome this

A

Tau is in multimeric form

Inhibit tau assembly
Degrade existing aggregates
HSP90 => increase proteasome-mediated clearance
Enhancers of autophagy

39
Q

What are the three Alzheimer’s disease hypotheses?

A
  1. Cholinergic hypotheses
  2. Amyloid hypotheses
  3. Tau hypotheses
40
Q

Explain the reasons for cholinergic hypotheses

A

Reduced levels of ACh present in patients with AD

41
Q

Explain the reasonings for the amyloid hypotheses

A

Extracellular aggregation of amyloid beta deposits resulting in plaque formation (Apo E assoc.)

42
Q

Explain the tau hypotheses

A

Formation of Intracellular NFTs and disintegration of neuronal transport system

43
Q

Explains methods of disruption of microtubules (3)

A

Axonal swellings accumulate => impairs axonal transport
Reduction in kinesin 1 motor protein promotes development of axonal defects and increases beta amyloid peptide levels and amyloid deposition (plaques)
NFT density has been observed to be associated with cognitive decline in AD

44
Q

What causes the pathological aggregation of tau?

A

Amyloid appears to be responsible for the cellular dysfunction that initiates the generation of misfolded tau.

45
Q

Features of Pre-senilin 1

A

A mutation in PS1 is the most common cause of AD
Important part of y-Secretase proteins
Mutation results in increased cleavage of APP in AB42
PS1 interacts with the glycogen synthase kinase Beta Which in turn phosphorylates kinesin light chains

46
Q

Phosphorylation of KLC’s causes the release of _________ from membrane bound organelles and thus reduces _____ _________.

A

Kinesin 1
Axonal transport

47
Q

APP, which acts as a kinesin 1 cargo receptor, depends on __________ for normal localisation and processing.

A

KLC1

48
Q

Loss of KLC1 causes early and selective _____ _________ defects of APP vesicles.

A

Axonal transport

49
Q

Relatively benign reduction in Kinesin 1 is __________ to impair axonal transport

A

Sufficient

50
Q

Axonal swelling an accumulation of cytoskeletal proteins, enhanced by 1️⃣ leads to increased 2️⃣

A

1️⃣ reduction in Kinesin 1
2️⃣ Beta amyloid protein generation

51
Q

Describe how mitochondrial transport is impaired in AD

A

Abnormal transport => synaptic starvation => inefficient clearance
Synaptic degeneration and neuronal decay

52
Q

Microtubules

A

Tracks
Essential for transport
Heterodimers of alpha and beta subunits -> dimerise to form protofilaments -> hollow tube of 13x protofilaments
Polar -> alpha Tubulin cap is positive; beta tubulin cap is negative
Treadmilling

Tissue Pathology (6 decks)

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