Neuronal Homeostasis

Question 1

What is meant by a chronic condition and provide some examples

Answer 1

Chronic conditions occur over long periods of time and are often progressive

Some examples of chronic conditions include; Alzheimer’s, Parkinson’s, Huntington’s and Prion’s disease

Question 2

What are acute diseases and provide some examples

Answer 2

Acute diseases are often injury related and are short term

For example; Spinal cord injurt, Stroke and Traumatic brain injury

Question 3

Neurodegenerative diseases are around what?

Answer 3

Neuronal dysfunction and neuronal death

Question 4

LO

Answer 4

• Be familiar with the structure and function of a neurone
• Understand the homeostatic processes within neurones
• Appreciate the problems that neurones face
• Be familiar with the mechanisms by which neurones become dysfunctional in neurodegenerative diseases

Question 5

What can happen to the brain neuronal circuitry as we age?

Answer 5

• Pruning of synapses/ plasticity
• Degenration e.g., glia or the circuit its self

Think about what in the circuit makes us vulnerable to disease…?

Question 6

What is meant by synaptic pruning?

Answer 6

Synaptic pruning is a natural process that occurs in the brain between early childhood and adulthood. During synaptic pruning, the brain eliminates extra synapses.

Synaptic pruning is thought to be the brain’s way of removing connections in the brain that are no longer needed.

Question 7

Neurons are polarised cells, what does this mean and how does this feature help?

Answer 7

Neurones are polarised cells this means that it has parts of it that are different e.g., dendritic structures and other structures

This means they have distinct functional regions: dendrites, soma, axon, and synapse

This helps because it provides a division of labour and helps with directionality (can go the other way in certain circumstances)

Question 8

What are some of the key features in a neuron?

Answer 8

Soma

Axon

Synapse

Question 9

Tell me the main roles of a soma

Answer 9

Receives input from other neurones

All housekeeping activities occur here (has nucleus, transcription, translation etc.,)- has high energy demand

Materials destined for distant areas dispatched

(materials= neurotransmitters is one of the key materials synthesised in the cell body for transport into the axon)

Question 10

Tell me the main roles of axons

Answer 10

Axonal transport of NTs occurs over microtubular tracks

Motor proteins (kinesin and dynein) propel cargo forward (ATP- provided by mitochondria)

Conduct electrical impulses- hence myelinated

AP generated in the axon and is propagated along the axon (helped by myelin and nodes of Ranvier)

Neural filaments and cytoskeleton’s role in the axon?

Question 11

Tell me the main roles of synapses

Answer 11

• Neuron’s business end
• NTs released to communicate with target (ATP)
• Retrograde signalling

Question 12

How does the structure of the synapses help with its function?

Answer 12

Structure allows function to occur because has high conc. Of voltage gated Ca2+ channels,

has postsynaptic and presynaptic and auto receptors to regulate and modulate NT release (controlled process)

short synaptic cleft

huge amount of mitochondrial need to generate lots of energy for the high NT release

Question 13

What is retrograde signalling and what type of information does it transmit?

Answer 13

Retrograde signalling: signalling that goes backwards (post- –> pre-synaptic neuron).

The kind of information that is sent is when it’s requires more NT due to a high demand for it

Signals go back to preserve the circuit

Question 14

When can retrograde signalling become a problem?

Answer 14

This becomes a problems when an individual has impaired retrograde signalling, then the pre-synaptic neuron may not get the signals it requires to stay alive

Could have something which retrogrades and then causes damage to the structure

Progression of neurodegenerative diseases (less activity in downstream circuit which has a negative effect on upstream circuit)

Question 15

What is homeostasis important for?

Answer 15

For keeping the systems regulating at an optimal level

Question 16

Give some examples of homeostatic pathways in neurons

Answer 16

• Ubiquitin proteosome pathway
• Endosomal/ lysosomal system
• Retrograde signalling

Question 17

Tell me about the ubiquitin proteosome pathway

Answer 17

Ubiquitin proteosome pathway: proteolytic degradation of damaged or misfolded proteins after ubiquitination (UQ added as a tag)

Question 18

Tell me about the endosomal/ lysosomal system

Answer 18

Endosomal/ lysosomal system: Internalisation of misfolded or abnormal proteins followed by enzymatic degradation

Question 19

Tell me about retrograde signalling

Answer 19

Retrograde signalling: neurotrophic factors (trophic support) and importins (retrograde injury signalling)

Question 20

Give an example of some diseases that can occur when these homeostatic mechanisms go wrong

Answer 20

How do these go wrong in diseases and the homeostatic mechanisms aren’t kept at their optimal levels…?

i.e., Stroke and oxygen and glucose levels impaired

At cellular levels the ion channel disruption such as sodium channel dysfunctions where they aren’t activated as easily leaving the individual with a high pain threshold, mitochondrial dysfunction with Parkinson’s disease

Question 21

The ubiquitin pathway can cause the formation of misfolded proteins. What can these proteins cause to happen and why don’t we want them present? What sort of effects can they cause?

Answer 21

Don’t want misfolded proteins in cytoplasm; these proteins act as a template and causes those proteins which are working normally (naïve proteins) to be converted and start producing the wrong function

(e.g., AD, PD, HD has aggregates of misfolded proteins in the neuron and accumulating becoming bigger. This is bad not only because of conversion of normal proteins but can also get in the way of synaptic transmission and other functions of the neurone).

Many of these misfolded proteins can jump over the synapse into the next cell and cause disruption in cells and their adjacent cells.

Question 22

What is some evidence of the presence of misfolded proteins?

Answer 22

Evidence of these misfolded proteins are; all these structures have UQ which are saying ‘eat me’ so system is trying to remove them unsuccessfully

Question 23

Why do the neuronal circuits in the older generation have more proteins being misfolded?

Answer 23

Older circuit in the older generation, have more proteins being misfolded and not the same capacity of the systems. Therefore, is unable to deal with misfolded proteins. At the molecular level it may be overworked or lose function (age related decline in optimal functioning)

Question 24

What are some of the problems that many neurons face?

Answer 24

Transport problems

Protein turnover problems

Synapse Vulnerability

High demand for energy

Question 25

Tell me about the transport problems faced by neurones. What diseases are implicated by this?

Answer 25

Transport problems: long distances, no homeostatic support en-route, slow (axonal transport disrupted in AD + HD)

Question 26

Tell me about the protein turnover problems faced by neurones. What diseases are implicated by this?

Answer 26

Protein turnover problems: proteins deposits may overwhelm UPS; abnormal prns resistant to UPS (inadequate protein turnover implicated in AD/ HD/ PD)

Question 27

Tell me about the synapse vulnerability of neurones. What diseases are implicated by this?

Answer 27

Synapse vulnerable: far away from soma and no obvious homeostatic support mechanisms along the axon which could detect misfolded proteins, limited homeostatic support, high energy consumer (synaptic dysfunction implicated in AD/ HD/ CJD)

Question 28

Tell me about the problems of the high demand for energy of neurones and what diseases are implicated by this?

Answer 28

High demand for energy: prone to oxidative stress (oxidative stress associated with most neurodegenerative diseases)

Question 29

Summary

Answer 29

• that neurones are polarised cells, and each region of the cell is engaged in a specific function
• neurones employ several mechanisms to degrade misfolded or damaged proteins
• retrograde signalling provides neurotrophic support and communicates injury messages
• neurones are vulnerable to axonal transport disruptions, accumulation of misfolded prns, synaptic dysfunction and oxidative stress.