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Question asked by: romyschulten - 2 years ago

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Maak een oefenexamen van de volgende tekst: What is neurodegenerative disease?
- Loss of specific brain functions
- Loss of synapses and neurons
Protein aggregates
- Monomer natively unfolded B-sheet nucleus amyloid fiber abnormal protein
aggregates
- Loss of function
- Gain of toxic function
- Protein quality control niet goed gevouwen eiwit wordt herkent door chaperones
eiwitten zorgen ervoor dat eiwitten die niet goed gevouwen zijn en chaperone
eiwitten zorgen ervoor dat het eiwit niet kan klonteren soms lukt niet en dan
ubiquitine aan eiwit gezet afbraak machine
- Afbraak Machine: ubiquitin-proteasome system (UPS) proteasome herkent
vlaggetje (ubiquitin) al aan elkaar plakt dan past het niet
- Autophagy: omcirkelen van materiaal wat afgebroken moet worden double
membrane wrapped around substrate fusion with lysosome
- Proteasome: only monomeric proteins
Causes of aggregate formation
1. Increased formation of misfolded proteins overexpression, mutation, stress, aging
2. Failure of protein quality control
3. Oligomers/fibers
4. Genetic and sporadic
5. Neuro-inflammation
Fibril formation and disease are connected but not quantitatively
- Many deposits but little or no disease
- Little or no deposits but severe disease
- Aggregation state is important for toxicity
Neurodegenerative disease aetiology
- Sporadic
- Increased levels of the protein by failing quality control
- Genetic earlier onset
- Increased levels of the protein by mutation in the DNA
- Mutation in the DNA that induces misfolding in protein
- Mutation found in
- Genes that encoded the main component of aggregate
- Genes that encoded other proteins: clue to mechanism
Protein aggregation (in cel of buiten) synaptic dysfunction neuronal loss
Neuroinflammation: microglia and astrocytes
- Microglial activation: a double edged sword
Dementia: combinations of dysfunction in multiple cognitive and behavioural domains
- Alzheimers disease most common
Alzheimers disease is a progressive neurodegenerative disease
- Loss of memory
- Loss of orientation in time and space
- Language difficulties
- Behavioural changes
- Personality changes
- Primary affected areas: hippocampus and cortex amyloid beta: plaques and tau
protein tangles
Plaque formation amyloid precursor protein APP processing
- APP is processed by enzymes called secretases to generate AB
- Sequential cleavage by B- and gamma-secretase
- Aggregation and deposition in plaques extracellular
Tangle formation: tau hyperphosphorylation and aggregation
- Tau: microtubule binding protein, stabilizes microtubules, dynamic phosphorylation
- Hyperphosphorylation: microtubule destabilization, tau aggregation (intracellular)
- Tangles: loss of function of tau
- Toxic gain of function
Inclusion in AD brain are ubiquitin positive
- Mutations in tau cause frontotemporal dementia not Alzheimer
Microglial activation recruited and activated by plaques
Parkinsons disease
- Bradykinesia
- Rigidity
- Resting tremor
- Postural instability
- Motor dysfunction
PD primary affected area: substantia nigra loss of dopaminergic neurons
SPECT scan ligand to dopamine transporter visualising loss of dopaminergic cells in live
patients
Pathology
- Neuronal inclusions: lewy bodies, aggregates of a-Synuclein (cytosol)
- Different modes of inheritance
- Many genes apart from alpha synuclein
Microglial response in PD more amoeboid microglia in PD
Treatment for Parkinsons disease: supplementation of dopamine
Huntingtons disease
Genetic only: repeat expansion in the Huntingtin gene CAG voor glutamine
- Aggregates of Huntingtin protein
- In the nucleus
- Affected brain area: striatum

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