Neurodegeneration Flashcards
What are the symptoms of Parkinson’s disease?
- Tremor
- Increased muscle tone
- Increased thalamul cortical activity
- Bradykinesia: slower movement
- Rigidity of the limbs.
What is that pathology of Parkinson’s disease?
Loss of the pigmented neuromenalin containing substantial nigra.
Dopaminergic pathways that project from the substantia nigra to the striatum is what is lost:
• 50 % loss of neurons in the substantia nigra for symptoms
• 80+ % loss at autopsy (death)
Overall effect of losing the dopaminergic pathway is a reduced thalamic output and therefore reduced movement.
Cell loss: • Substantia nigra • Locus ceruleus • Dorsal motor nucleus of the vagus • Raphe nuclei • Nucleus basalis
Lewy bodies: • Spherical 8-30 um • Intracellular • Eosinophilic core • Pale halo • Filaments, granular material • Neurofilament proteins: ubiquitin and synuclein • Many other proteins and lipids are present.
What is the ‘cause’ of Parkinson’s Disease?
A large number of genes (at least 15) have been found that give rise to familial forms of Parkinson’s disease:
Four to focus on: all particular involved in protein trafficking and ubiquitination
• SNCA
• PARKIN
• UCHL1
• LRRK2.
What is alpha-synuclein?
A 140 amino acid protein, found largely in the pre-synaptic terminal.
- Suggested involved in synaptic plasticity, membrane trafficking and vesicle sorting
- Mutations can lead to Parkinson’s disease and expression of more than one gene (gene replication)
- Highly agregable and can be found in the amyloid plaques in Alzheimer’s disease.
- Suggesting its aggregation and deposition is a key step in Parkinson’s disease progression.
Describe LRRK2?
- 2527 amino acids long kinase proteins
- Involved in cell division and neurite outgrowth
- Found in SN
- Found in striatum
- Reduced in Parkinson’s disease.
Describe UCHL1?
Ubiquitin carboxyl-terminal hydrolase 1 • Deubiquitin enzyme: deubiquitinates proteins, important in the proteasomal system as they are required to be deubiquitinated before degradation by the lysosome • Cleaves C-terminal bond • Mutant causes PD • Decreased deubiquitin activity • Present in Lewy bodies.
Describe Parkin?
- 465 amino acids
- Ubiquitin ligase enzyme- an enzyme that stiks the ubiquitin onto a protein
- Can bind and ubiquitinate α-synuclein
- Ub/proteasome system
- Found in Lewy bodies
- Protective? Excess α synuclein targetted to proteasome? Protects SN neurones from α synuclein toxicity.
What are the possible surgical treatments of Parkinson’s Disease?
Neural transplantation, fetal neural transplantation, stem cell transplantation, deep brain stimulation, gene therapy, growth factors.
What disease is caused by amyloid plaques?
Alzheimer’s Disease.
Describe the amyloid cascade?
- A gene or environmental event will cause an amyloid beta peptide accumulation
- Neuronal injury will occur for some reason causing neuronal dysfunction and death
- Plaques would form
- There would be altered Tau metabolism
- All would lead to dementia.
What is the most promising biomarker for Alzheimer’s Disease?
Imaging amyloid plaques in the human brain in early stages but currently plaque content in the brain cannot be a diagnosis of Alzheimer’s disease. You can also look at Tau using tau binding agents.
What mutations are inherited in familial Alzheimer’s Disease?
Mutations in presinillin-1 and 2 and APP.
Describe the mutation of Presinilin-1 which causes Alzheimer’s Disease?
Mutations occur in the precursor protein near the amyloid beta region itself these alter secretase cleavage of increases aggregation.
Describe the protective mutation found for Alzheimer’s Disease?
Impairs the ability of beta secretase to bind onto and cleave the precursor protein.
What are current drugs of Alzheimer’s Disease?
NMDA receptor antagonist, eg. Ebixa.
Cholinesterase inhibitor, eg. Aricept, Exelon, Remvinyl.
What do the current drugs for Alzheimer’s Disease do and what is required?
They only temporally relive symptoms, no cure. Disease modifying drugs are required. There are problems with crossing the BBB.
What do new drugs for Alzheimer’s Disease focus on?
Inhibition of gamma-secretase, inhibition of beta-secretase, activation of alpha-secretase, altering APP trafficking, activation of amyloid beta-degrading enzymes, immunotherapy (vaccination).
What is the current state of Alzheimer’s drugs?
In the last 10 years no new Alzheimer’s drugs have emerged from clinical trials. It takes >10 years and $2billion to bring a new drug into clinical use.
What are the possible protective factors for Alzheimer’s Disease?
- Education and occupation
- Use it or lose it
- Physical exercise
- Social networks
- Anti-oxidants: Vit C, Vit E, curcumin, blueberries, cocoa, red wine
- Mediterranean-style diet
- Oily fish (omega 3)
- Vitamins B6, B12, folate
- Plant sterols & reduced cholesterol.
Describe tau protein?
- Microtubule associated protein
- Largely localised to neuronal axons
- Important biological role in stabilising microtubules through promoting microtubule polymerisation
- Aid in neuronal structure and axonal transport.
Describe tau phosphorylation?
Phosphorylation at a range of serine and threonine residues, negatively regulates the binding of tau to MTs. Hyper-phosphorylation impairs normal functions and forms paired helical filaments (PHF).
What are PHF and what does dysfunction of PHF cause?
PHF are building blocks of neurofibrillary tangles (NFT) 8-20 nm. Dysfunction causes pathogenies and related neurodegenerative diseases- diagram. No ones knows the cause of hyper-phosphorylation.
Describe Pick inclusion bodies?
Tau-positive spherical cytoplasmic neuronal inclusions, composed of straight filaments.
Describe perinuclear inclusions?
Aggregations of Huntington in the frontal cortex.
What disease are related to tau?
Many, including Alzheimer’s, dementia, picks etc.
What types of tau mutations are there?
Three groups: those that impair function, those that promote aggregation and those that alter splicing.
