Neurological Disease- Intro and Parkinson's Flashcards
What are neurodegenerative diseases?
A group of diverse disorders that are characterised by a progressive loss of neurons in specific regions of the CNS
What do clinical symptoms of neurogenerative diseases depend on?
Clinical symptoms depend on neurons that are affected
Onset of neurodegeneration usually precedes clinical manifestations by years/decades
Increasing evidence due to aging population
What is the function of neurons?
Neurons receive, interpret and transmit information
Carry information
Co-ordinate response
What are the types of neurons?
Motor neurons
Sensory neurons
What is the structure of a neurone?
Cell body
Nucleus
Axon
Cell membrane
Myelin sheath
Axon terminal
What is the function of the cell body and dendrite in neurons?
Cell body- Contains nucleus and other cell organelles
Protein synthesis
Dendrite- Receives stimulus
What is the function of the axon and myelin sheath in neurons?
Axon- Transmits stimulus away from cell body to other cells
Myelin sheath- Lipid rich layer surrounding axon, increases speed of impulse conduction
How are electrical signals transmitted?
Electrical signals (nerve impulses) are transmitted by chemical messengers (neurotransmitters) to the next cell
Communication of information between cells occurs via a synapse
What do neurotransmitters do?
Neurotransmitters transmit chemical messages from one neuron to another across the synapse
Message is communicated from the pre-synaptic cell to a post-synaptic cell
What are some neurotransmitters?
Acetylcholine
Dopamine
Noradrenaline
Serotonin (5-HT)
Glutamate
GABA
What is the function of a synapse?
To allow communication between neurons or between neurons and another type of cell. It is the critical where information is transmitted within the nervous system
What are glial cells?
Provide support for neuron function
Glial cells outnumber neurons
Most abundant cell in the CNS
What are microglia?
Resident macrophage in brain
Remove debris (e.g. dead cells)
Defence
What are some examples of glial cells?
Microglia
Oligodendrocytes
Astrocytes
What are oligodendrocytes?
A type of glial cell
Formation of myelin sheath in CNS
What are astrocytes
The dominant glial cell and perform many functions
e.g. they form the blood brain barrier, provide nutrients to neurons and give synapses structural support
What is parkinson’s disease?
Progressive neurodegenerative disease
Characterised primarily by abnormalities in movement (motor disorder) and cognitive impairments can also occur
2nd most common neurodegenerative disease
150,000 people in UK have parkinson’s
What is the prevalence of parkinson’s?
1% of over 60’s
4% of over 80’s
What are the clinical symptoms of parkinsons?
Bradykinesia- slowed movement
Rigidity- Muscle stiffness which limits range of motion
Tremor- uncontrollable shaking
Postural instability- Posture becomes stooped, problems with balance
What are the pathological hallmarks of PD?
Profound and selective loss of dopaminergic neurons
Presence of intra-neuronal (cytoplasmic) inclusions of aggregated protein (Lewy bodies)
What causes the loss of dopaminergic neurons in PD?
Loss of dopaminergic neurons in the substantia nigra pars compacta (SNpc)
Dopamine is a neurotransmitter
SNpc controls the initiation and execution of movement
Loss of dopamine neurons causes motor symptoms
Clinical presentation of disease when 50-70% neurons degenerate
What is the unknown hallmark of PD?
The molecular basis underlying neuron loss and Lewy body function is not completely understood
Is familial PD common?
Familial and sporadic forms are often indistinguishable
Gene mutations responsible identified
Familial forms of PD provide an indication of the potential molecular mechanisms underlying disease development
However, familial cases are rare (10%)
What are the different hypotheses for PD pathogenesis?
- Protein aggregation (Lewy bodies)
- Mitochondrial dysfunction
- Free radical injury (oxidative stress)
What is the hypothesis of protein aggregation in PD?
Formation of Lewy bodies is a pathological hallmark of PD
Intracellular (cytoplasmic) inclusions formed from the accumulation of aggregated protein
Major constituent is alpha (alpha)-synuclein
What is alpha-synuclein?
Pre-synaptic, cytoplasmic protein
Role in:
Storage and compartmentalisation of neurotransmitters
Maintaining mitochondrial integrity
What does the presence of alpha-synuclein in Lewy bodies?
Suggests that this protein is important to PD, protein aggregates thought to acquire toxic properties
Mutations in the alpha-synuclein gene are observed in familial forms of PD
Presence of Lewy bodies (protein aggregates) likely to contribute to neuronal dysfunction and loss
What might PD pathogenesis involve dysfunction in?
The Ubiquitin-proteasome system (UPS)
The UPS is responsible for the destruction of proteins
Proteins are constantly turning over
Broken down into constituent amino acids and replaced with new proteins
What 2 steps do mis-folded and damaged proteins go through in the UPS?
- Covalent attachment of multiple ubiquitin (protein) molecules to substrate (target protein)
- Proteolysis- the ubiquitin-tagged protein is recognized, unfolded, and degraded into peptides by the 26s proteasome, while ubiquitin is recycled
What gene is usually seen to be mutated in familial cases of PD?
In the gene for parkin protein
Parkin gene encodes a ubiquitin ligase
Catalyses the addition of ubiquitin to proteins (substrate)
Neuroprotective protein
What does a mutation in parkin gene lead to?
Loss of function mutation in parkin gene leads to an accumulation of neurotoxic parkin substrates in neurons
Could cause cell death
Substrates not identified yet
How is PD associated with mitochondrial dysfunction?
Mitochondria are abundant in tissues with high energy demands
Mitochondria are a source of ROS in cells
Mitochondrial dysfunction increases ROS production
What does the postmortem tissue of substantia nigra in PD patients have?
Increased levels of lipid peroxidation, high oxidation of proteins and DNA, lower glutathione (antioxidant) levels
What do the levels of oxidation in substantia nigra in PD patients suggest?
Suggests that oxidative stress contributes to PD pathogenesis
Mitochondrial dysfunction could promote oxidative stress to cause cell death in PD
How is the electron transport chain related to PD patients?
Complex 1 is the first enzyme in the system
Dysfunction/inhibition of complex 1 activity in PD patients
Mutations in complex 1 in PD
How does dysfunction in complex 1 in ETC affect PD patients?
Impairments in complex 1 activity in PD enhances ROS production by mitochondria
Also decreases mitochondrial activity
Less ATP production
Proposed mechanism for dopaminergic neuron death
What is MPTP?
Abuse of drug MPTP
1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine
This drug causes mitochondrial dysfunction in dopamine neurons
Selective irreversible degeneration of dopaminergic neurons (SNpc)
What is MPTP’s mechanism of action?
MPTP cross the BBB
Converted to a neurotoxin metabolite (MPP+) by astrocytes
Internalised into the pre-synaptic terminal of dopamine neurons
Transported into mitochondria
Where it inhibits complex 1 of the ECT
What other causes are there of inhibition of complex 1 activity?
Environmental factors
- Pesticides
- Epidemiology and animal studies identified link
What can MPTP be used to generate?
PD animal models:
- To test efficacy if therapeutics
- Used to better understand disease pathology
What is PINK-1?
It is a mitochondrial protein with kinase activity
Helps maintain mitochondrial integrity
Protects from Ox stress
Targets damaged mitochondria for degradation
Neuroprotective properties
What does loss of function in PINK-1 cause?
Occurs in familial cases of PD
Leads to mitochondria dysfunction
More susceptible to ox stress
Promotes loss of neurons
What have animal studies showed in regards to PD?
Have shown that exposure to pesticides which impair mitochondrial function can increase risk of PD
What other mutation is evident in familial PD?
Loss of function DJ-1 mutations
Multi-functional protein
Neuroprotective
Antioxidant
What does reduced DJ-1 activity cause?
Reduced DJ-1 activity in PD enhances cell death
Leads to ROS generation
Neurons predisposed to oxidative damage
What’s important when treating PD?
Timing of treatment is likely to impact on success
Ideally, to be effective treatments need to be administered before widespread destruction of nerves
Is there a cure for PD?
No cure for PD: no treatment to stop or reverse the neurodegenerative process
Patients progressively get worse
What can be used to manage symptoms of PD?
Pharmaceuticals manage symptoms
Dopaminergic drugs
Treatment is centered on restoring dopamine
What is Levodopa (L-Dopa)?
Is used as a first line treatment for PD
Precursor to dopamine
Dopamine cannot be given orally as it cannot cross the BBB
Converted to dopamine in the brain by dopa decarboxylase
What is L-Dopa often given in combination with?
Given in combination with peripheral dopa decarboxylase inhibitor to increase delivery of L-Dopa to the brain and increased duration of action
What is MAO?
MAO is an enzyme that breaks down neurotransmitters
Inhibitors of MAO activity increase the level of dopamine in the synapse
Selegiline is a MAOI used to treat PD
What are dopamine reuptake inhibitors?
Inhibit dopamine re-uptake into the pre synaptic nerve terminal
Prolong duration of action of dopamine
Can also stimulate dopamine release from nerves
What are dopamine agonists?
Dopamine receptor agonsists (e.g. Bromocriptine) are used if L-Dopa is not effective
They bind to dopamine receptors in the brain, stimulating the dopamine system
Lose effectiveness over time
Side effects more serious than L-Dopa
How is PD diagnosed?
Pathological hallmarks only evident at post mortem
Inherited conditions can be identified
Clinical features and responsiveness to dopamine replacement therapy used for diagnosis
