Nerve

Question 1

Define retrograde movement

Answer 1

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

Question 2

Anterograde Movement

Answer 2

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

Question 3

Features of Dyneins

Answer 3

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

Question 4

The dynactin complex consists of at least __ subnets.

Answer 4

8

Question 5

List two important subunits of dynactin

Answer 5

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

Question 6

Kinesins can be…

Answer 6

…monomers, homodimers, heterodimers…

Question 7

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

Answer 7

Motor and Tail

Question 8

Kinesin motor protein features

Answer 8

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

Question 9

Motor protein walking

Answer 9

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

Question 10

Define proteostasis

Answer 10

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

Question 11

What are the potential fates of newly synthesised proteins?

Answer 11

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

Question 12

What is ubiquitin?

Answer 12

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

Question 13

What are proteasomes?

Answer 13

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

Question 14

Protein(s) associated with Parkinson’s disease

Answer 14

Alpha synuclein

Question 15

Protein(s) associated with Alzheimer’s disease

Answer 15

Amyloid beta and Tau

Question 16

Protein(s) associated with Multiple Taupathies

Answer 16

Tau (MT ass.)

Question 17

Protein(s) associated with Huntington’s Disease

Answer 17

Huntingtin with tandem glutamine repeats

Question 18

Features of Alzheimer’s disease

Answer 18

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

Question 19

Features of beta amyloid

Answer 19

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

Question 20

Beta Amyloid Functions

Answer 20

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

Question 21

List the Antimicrobial activity of amyloid beta

Answer 21

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

Question 22

Describe the Antimicrobial nature of beta amyloid

Answer 22

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

Question 23

Describe the tumour suppressive nature of beta amyloid

Answer 23

Beta amyloid may intercept oncogenes viruses and suppress tumour growth

Question 24

How does amyloid beta seal leaks in the BBB?

Answer 24

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

Question 25

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

Answer 25

Beta Amyloid

Question 26

What are the extracellular protein aggregates in AD?

Answer 26

AB plaques (Neurotic plaques and extracellular lesions)

Question 27

What are the intracellular protein aggregates in AD?

Answer 27

Neurofibrillary tangles (MAPs -> NFTs)

Question 28

5 stages in the formation of a B-Amyloid Plaque

Answer 28

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

Question 29

Features of Tau

Answer 29

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

Question 30

Describe the two mechanisms that allow tau to control MT

Answer 30

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

Question 31

Name an indirect meachanism of tau hyperphosphorylation

Answer 31

Oxidative stress

Question 32

List two direct mechanisms of tau hyperphosphorylation

Answer 32

Mutations Down-regulation of phosphatases

Question 33

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

Answer 33

MT detachment Loss of stabilising function Change in dynamics (This is a cycle of events)

Question 34

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

Answer 34

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

Question 35

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

Answer 35

Greater Beta Amyloid plaques

Question 36

What does changes in MT dynamics lead to?

Answer 36

Compromised axonal transport (neurotoxicity)

Question 37

Methods to target tau therapeutically

Answer 37

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

Question 38

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

Answer 38

Tau is in multimeric form Inhibit tau assembly Degrade existing aggregates HSP90 => increase proteasome-mediated clearance Enhancers of autophagy

Question 39

What are the three Alzheimer’s disease hypotheses?

Answer 39

1. Cholinergic hypotheses 2. Amyloid hypotheses 3. Tau hypotheses

Question 40

Explain the reasons for cholinergic hypotheses

Answer 40

Reduced levels of ACh present in patients with AD

Question 41

Explain the reasonings for the amyloid hypotheses

Answer 41

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

Question 42

Explain the tau hypotheses

Answer 42

Formation of Intracellular NFTs and disintegration of neuronal transport system

Question 43

Explains methods of disruption of microtubules (3)

Answer 43

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

Question 44

What causes the pathological aggregation of tau?

Answer 44

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

Question 45

Features of Pre-senilin 1

Answer 45

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

Question 46

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

Answer 46

Kinesin 1 Axonal transport

Question 47

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

Answer 47

KLC1

Question 48

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

Answer 48

Axonal transport

Question 49

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

Answer 49

Sufficient

Question 50

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

Answer 50

1️⃣ reduction in Kinesin 1 2️⃣ Beta amyloid protein generation

Question 51

Describe how mitochondrial transport is impaired in AD

Answer 51

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

Question 52

Microtubules

Answer 52

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