Parkinson's Flashcards
List the different anti-parkinsonian drugs and their modes of action.
D2 receptor agonists:
Bromocriptine, pergolide (Ergot)
Ropinirole, rotigotine (non-ergot)
MAO-B Inhibitors
Selegiline, Rasagiline
COMT inhibitors
Sinemet, Madopar
L-DOPA: Bypasses L-tyrosine in synthesis pathway.
What are the 4 degeneration mechanisms in parkinsons?
- Ubiquitin proteasome pathway disruption
- ROS- Mitochondrial abnormalities cause uncoupling of redox reactions- ROS generation. SN in Parkinson’s may be deficient in antioxidants e.g glutathione.
- Neuroinflammation: Microglial activation. Neurotoxins can activate microglia. (indirect, mixed mode & direct neurotoxins)
- Mitochondrial dysfunction. Inner membrane integrity lost. Release of cytochrome c.
Which TFs are implicated in controlling neuronal vulnerability during development?
- Nurr1. (maintains neurotransmitter levels)
- FoxA2: KO mice lost neurons in SN only.
- Engrailed: All DA neurons lost without 4 alleles.
Therefore, vulnerability is exposed through reduced developmental TF expression and loss likely mediated through mitochondrial dysfunction.
What is the difference in vulnerability between SN & VTA neurons?
SN neurons more vulnerable. VTA neurons express more G substrate, & other protective TFs.
Which gene mutations are present in PD?
Alpha-synuclein: Normally involved in synaptic vesicle function. Hyperphosphorylated & Ubiquitinated in Lewy bodies. Misfolded form toxic to neurons?
Parkin: E3 ligase, addition of ubiquitin to proteins. Loss of parkin->failure to break down damaged proteins
Pink-1: Targets to mitochondria. KO causes mito dysfunction, reduced respiratory chain activity, reduced ATP in tissues.
DJ1: Targeted to mitochondria. Inhibits a-synuclein aggregation via chaperone activity. Modulates mitochondrial membrane potential & enhances energetics.
What are the disease correlates of the following neuropathological markers?
a-synuclein
Tau
TDP-43
Non specific
Vascular
Toxic
Drug Induced
Infectious
Why are SN neurons physiologically less vulnerable than VTA DA neurons?
SN neurons are involved in movement- pacemaker like properties. This involves frequent intracellular calcium transients, which isn’t buffered, making them prone to neurodegeneration.
VTA neurons have no transients, less Ca2+ density, high calbindin to protect cells.
What are the 6 braak stages in parkinsons?
1: Olfactory bulb, Dorsal motor nucleus
2: Locus coeruleus & Raphne. Sublaterodorsal nucleus.
3 & 4: SNc, pars compacta, Basal forebrain.
5 & 6: Invades neocortex, spreads into different lobes.
What are the 5 genes that are altered in parkinson’s?
- Synuclein
- LRRK2 (interacts with parkin)
- Parkin (E3 ligase, tags proteins. Mitochondria turnover)
- PINK1 (protects cells from stress induced mitochondrial dysfunction- induces autophagy)
- FJ-1 (redox sensitive chaperone, stabilises mito membrane potential)
What is the normal function of a-synuclein & what happens when it is dysregulated?
Involved in SNARE complex formation and neurotransmitter release.
Without synuclein, vesicles not released and become trapped- neurotransmitter leaks (dopamine) which oxidises. This causes free radicals.
What negative effects does unfolded a-synuclein have?
Proteasome function
Mitochondria complex I inhibition
Autophagy inhibition
Membrane transition pore more leaky.
What is LRRK2 involved in and what is the most common mutation?
Mitochondrial function, inflammation, lysosome function, trafficking, autophagy/mitophagy, neurite growth and differentiation.
Most common mutation is G2019S.
What is GBA and which drugs target it?
Encodes glucocerebrosidase (GCase), which hydrolyses glucosylceramide into ceramide and glucose (breaks down lysosomes).
Ambroxole
Venlustat
List some risk loci (SNPs)
MAPT SNCA BST1 LRRK2 ACMSD STK39 HIP1R
What is the role of epigenetics in neurodegeneration?
Chromatin packaging determines accessibility of genome. More acetylation means more transcription.
In neurodegeneration, the balance is shifted to HDACs, so less transcription.
Which epigenetic changes are seen in parkinson’s?
DNA methyltransferases (DNMT1) : translocated out of nucleus in PD- results in hypomethylation.
Histone modification: a-synuclein promotes histone H3 hypoacetylation (masks H3)
What is an example of an HDAC inhibitor?
Valproate: Causes changes in histone acetylation
What is lactacystein and how was it used with valproate?
Lactacystein: Inhibits proteasome and induces neurodegeneration. Associated with histone hypoacetylation and reduced gene expression- causes lesions in mice.
Valproate with lactacystein lesion:
Neuroprotection seen with low dose valproate, high dose showed reversal of cell loss.
What are the 3 toxin based rodent models?
6-OHDA
MPT
Lactacystein
How does 6-OHDA work?
Induce oxidative stress and mitochondrial inhibition, iron accumulation and inflammation.
Dose responsive loss of nigrostriatal pathways.
How does MPTP work?
Lipophilic, penetrates BBB. Mitochondrial inhibition + Oxidative stress. No protein inclusions.
Loss of DA neurons in the nigra, VTA neurons intact.
Only effective in non human primates- causes akinetic, flexed posture, rigidity, clumsiness and tremor. MPTP converted to MPP+ in the primate brain.
How does the proteasome inhibitor lactacystein work?
Causes chronic progressive, nigral cell loss and inclusions. It causes lesions.
Describe some a-synuclein animal models.
Drosophila:
Few neurons and high turnover rate (easy to examine)
Selective neuronal death
Flies show ‘movement disorder’
Mice over-expressing wild type synuclein
Single mutation- no pathology.
2 mutations- pathology. Less stress and strains in mouse system so needs 2 mutations to set it off.
rAAV-a-synuclein model
rAAV viral vector transfects neurons to overproduce wild type a-synuclein. Loss of DA striatal terminals and cell bodies.
Deficits in motor behaviour
Pre formed fibrils
a-synuclein fibrils injected into striatum form inclusions
Cause native a-synuclein to misfold, and spread across brain with time.
How have iron chelators been used as a treatment?
Collects iron in the brain and removes it. Clinical trial in 2020.
Chelation therapy successful in B-thalassaemia (iron overload)
