Neuro - Parkinson's disease Flashcards
What are the symptoms of PD?
Akinetic-rigid syndrome Loss of movement Increased muscle tone Bradykinesia (slow movement) Rigidity Resting tremor Lack of ability to initiate movement Loss pigmented neuromelanin containing neurones of the subsrantia nigra
What is the direct and indirect pathway
Direct pathway:
GABAnergic projection from the striatum to the GPi
Indirect pathway:
Projects from the striatum to the GPi via GABAnergic neurones in the GPe and Glutaminergic neurones in the subthalamic nucleus (STN)
The neurones in the GPi are mainly GABAnergic and have an inhibitory influence on the VA-VL in the thalamus which project onto the motor cortex. This inhibitory output from the GPi is believed to restrain thalamocortical motor activity.
Under normal conditions the dopaminergic neurones in the substantia nigra supply the striatum with dopamine which stimulates D1 receptors (direct) and inhibits D2 receptors (indirect). The net result is reduced inhibitory output from the GPi acting on the thalamocortical motor circuit resulting in general facilitation of motor function.
What happens the PD pathway in the brain?
Loose the dopaminergic neurons in the substantia nigra and get decreased dopamine therefore decreased stimulation of D1 and D2 receptors leading to decreased activity of the direct pathway and facilitation of the indirect pathway which the net result is increased inhibitory output from the GPi resulting in decreased thalamocortical motor facilitation
Where do you get cell loss in PD?
Substantia nigra mainly but also locus ceruleus, dorsal motor nucleus of the vagus, raphe nuclei and nucleus basalis
What are Lewy bodies?
Spherical intracellular inclusion bodies composed of filamentous and granular material. Have an eosinophilic core and a pale halo. Made up of lots of different proteins but one of the main components is alpha-synuclein. Also contain lipids and Ubiquitin
How many genes have been found to give rise to PD?
At least 15 genes have found to be mutated
Which are the four genes focussed on?
PARK1/4 - SNCA (alpha-synuclein)
PARK2 - Parkin
PARK5 - UCHL-1
PARK8 - LRRK2
Can we use the familial forms of PD to inform us of the sporadic forms?
Yes as they have similar features - can tell us about them and inform us of potential drug targets
Where is alpha-synuclein present?
Presynaptic terminals
Describe alpha-synuclein
140aa protein found in presynaptic terminals
No clear function but involved in synaptic plasticity? Membrane trafficking and vesicle sorting?
Mutations in it can cause PD and gene replication can cause PD
Aggregable and also found in AD plaques
What is LRRK2?
LRRK2 - Leucine-rich repeat kinase 2 - complex protein of the ROCO family.
Mutations in this gene have been linked to familial forms of PD with the most common mutation being G2019S.
LRRK2 contains a MAPKKK (kinase effector domain) and ROC-COR domain (GTP binding regulatory domain).
The most common mutation is found in the MAPKKK domain and is part of a highly conserved DYG motif.
PD mutants of LRRK2 increase kinase activity leading to neuronal death.
LRRK2 is a GTP/GDP regulated protein kianse.
Mutations can cause P of its targets without regulation and in rats with was shown that LRRK2 mutants cause less neuronal branching and outgrowth.
Immunohistochemical staining for LRRK2 showed reduction of LRRK2 compared to a control patient.
Describe Parkin
Parkin is a 465aa Ub ligase enzyme
Can bind Ub and alpha-synuclein and Ub it for degradation
Was found by mutations
Under normal conditions it was found to be protective targeting excess alpha-syn to the proteosome
Can be found in lewy bodies
What happens if you remove the parkin gene?
Get a build up of alpha-syn in the cell which then leads to aggregation
How was Parkin shown to be protective?
Stained dopaminergic neurons red
Injecting one side and using the other side as a control
Overexpression of alpha-syn see a reduction in the number of dopaminergic neurones where as overexpression of Parkin see little loss of dopaminergic neurones. Expressing both together you get recovery
What is UCHL-1?
A de-Ub enzyme -before the protein has to be broken down the Ub has to be removed and UCHL-1 does this by removing Ub at the C-terminal bond Mutations cause PD or a PD-like syndrome It is a loss of function mutation Present in Lewy bodies Get decrease de-Ub activity
