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.
