Nerve Flashcards
Define retrograde movement
Movement of old components no endocytosis molecules from synapse to cell body for degradation/recycling
Anterograde Movement
Movement of molecules and protein in transport vesicles from cell body along axon
Features of Dyneins
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
The dynactin complex consists of at least __ subnets.
8
List two important subunits of dynactin
- A short actin-related protein (Arq1) that binds dynamitin essential for cargo binding
- P150glued - a protein that binds MT
Kinesins can be…
…monomers, homodimers, heterodimers…
What are the two most important sites within a motor protein?
Motor and Tail
Kinesin motor protein features
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
Motor protein walking
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
Define proteostasis
Balancing of cellular pathways that are responsible for protein synthesis, folding, processing, assembly, trafficking, localisation and degradation.
What are the potential fates of newly synthesised proteins?
Chaperoned to either the ubiquities proteosome system or the autophagy lysosome pathway
What is ubiquitin?
A 76 amino acid protein that can be covalently linked to lysine residues of proteins targeted for Intracellular degradation by proteasomes.
What are proteasomes?
Multimeric proteases with a barrel shaped core and a cap that recognises polyubiquitinated proteins
Protein(s) associated with Parkinson’s disease
Alpha synuclein
Protein(s) associated with Alzheimer’s disease
Amyloid beta and Tau
Protein(s) associated with Multiple Taupathies
Tau (MT ass.)
Protein(s) associated with Huntington’s Disease
Huntingtin with tandem glutamine repeats
Features of Alzheimer’s disease
Degeneration of neurons, particularly in basal forebrain and hippocampus
Synaptic pathology and altered neuronal connections
Features of beta amyloid
Derived from proteolytic processing of amyloid precursor protein
Peptides come together to form amyloid fibrils with filamentous structure
2 kinds AB40 and AB42
Beta Amyloid Functions
Antimicrobial activity
Tumour suppression
Sealing leaks in blood brain barrier (BBB)
Promoting recovery from brain injury
List the Antimicrobial activity of amyloid beta
Antibacterial, antifungal and antiviral properties effective against at least 11 species of microbe
Describe the Antimicrobial nature of beta amyloid
Antibacterial, antifungal, and antiviral properties effective against at least 11 different microbe species
Describe the tumour suppressive nature of beta amyloid
Beta amyloid may intercept oncogenes viruses and suppress tumour growth
How does amyloid beta seal leaks in the BBB?
AB binds blood-borne solutes together to form a plug that prevents the spread of neuro active and toxic components into the brain
The presence of ____________ results in better outcomes in recovery from brain injury in animal models.
Beta Amyloid
What are the extracellular protein aggregates in AD?
AB plaques
(Neurotic plaques and extracellular lesions)
What are the intracellular protein aggregates in AD?
Neurofibrillary tangles
(MAPs -> NFTs)
5 stages in the formation of a B-Amyloid Plaque
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
Features of Tau
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
Describe the two mechanisms that allow tau to control MT
- Kinase mediated phosphorylation - detaches tau from MT
- Dephosphorylation reaction by phosphates - restores MT binding ability
Name an indirect meachanism of tau hyperphosphorylation
Oxidative stress
List two direct mechanisms of tau hyperphosphorylation
Mutations
Down-regulation of phosphatases
Explain the mechanisms that lead to a loss of function due to hyperphosphorylation
MT detachment
Loss of stabilising function
Change in dynamics
(This is a cycle of events)
Explain the mechanisms that lead to a toxic gain of function of hyperphosphorylated tau
NFTs made up of hyperphosphprylated tau sequester normal tau
NFTs become physical obstacles to the transport of vesicles and other cargos
Tau aggregation has _______ implications than __________ due to its Intracellular effect.
Greater
Beta Amyloid plaques
What does changes in MT dynamics lead to?
Compromised axonal transport (neurotoxicity)
Methods to target tau therapeutically
Small molecule MT stabilising agents may compensate for reduction in tau interaction with MT
Inhibitors of tau kinases may improve MT function
Explain the difficulties of degrading tau enzymatically and potential methods to overcome this
Tau is in multimeric form
Inhibit tau assembly
Degrade existing aggregates
HSP90 => increase proteasome-mediated clearance
Enhancers of autophagy
What are the three Alzheimer’s disease hypotheses?
- Cholinergic hypotheses
- Amyloid hypotheses
- Tau hypotheses
Explain the reasons for cholinergic hypotheses
Reduced levels of ACh present in patients with AD
Explain the reasonings for the amyloid hypotheses
Extracellular aggregation of amyloid beta deposits resulting in plaque formation (Apo E assoc.)
Explain the tau hypotheses
Formation of Intracellular NFTs and disintegration of neuronal transport system
Explains methods of disruption of microtubules (3)
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
What causes the pathological aggregation of tau?
Amyloid appears to be responsible for the cellular dysfunction that initiates the generation of misfolded tau.
Features of Pre-senilin 1
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
Phosphorylation of KLC’s causes the release of _________ from membrane bound organelles and thus reduces _____ _________.
Kinesin 1
Axonal transport
APP, which acts as a kinesin 1 cargo receptor, depends on __________ for normal localisation and processing.
KLC1
Loss of KLC1 causes early and selective _____ _________ defects of APP vesicles.
Axonal transport
Relatively benign reduction in Kinesin 1 is __________ to impair axonal transport
Sufficient
Axonal swelling an accumulation of cytoskeletal proteins, enhanced by 1️⃣ leads to increased 2️⃣
1️⃣ reduction in Kinesin 1
2️⃣ Beta amyloid protein generation
Describe how mitochondrial transport is impaired in AD
Abnormal transport => synaptic starvation => inefficient clearance
Synaptic degeneration and neuronal decay
Microtubules
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
