Lecture 8 Neurology Theme - Parkinson's Disease and The Motor System Flashcards
What is Parkinson’s?
A progressive neurodegenerative hypo kinetic disorders characterised by hypo kinetic movement caused by the loss of dopaminergic neurons in the substantia nigra.
What is the substantia nigra?
A midbrain dopaminergic nucleus which modulates motor movement and the reward pathway in the basal ganglia circuitry.
What is the pathology of PD?
Diminished substantia nigra, neuronal loss and Lewy bodies remaining in nerve cells.
Neuromelanin is gone in PD.
50% of cells gone by the time symptoms arise.
How can we image the substantia nigra terminals?
PET
SPECT
MRI
CT
Can see pre-synaptic dopamine in synaptic vessels by 18F-Fluoro-DOPA receptor used in PET scans.
Briefly describe the pathway leading to PD.
Dopamine deficiency in the SN means the striatum is less excited and can’t inhibit the globus pallidus through the indirect pathway.
Globus pallidus becomes hyperactive and inhibits the subthalamic nucleus more so there is hyperactivity of the output nuclei and excess inhibition of the motor thalamus.
SN to the striatum is dopaminergic, everything else if GABAergic.
What is SNCA gene for and how is it implicated in PD?
SNCA gene encodes for alpha synuclein - chromosome 4p21 contains SNCA so a point mutation of gene/polymorphisms of a-synucelin promoter increase the risk of PD.
Describe alpha synucelin in PD.
A-synucelin is a normal protein that controls neutotransmitter release.
A-synucelin forms small oligomers which are toxic to neurons and there is evidence to show prion like spread.
The a-synucelin aggregates are hydrophobic and arise in the medulla, ascending through the brainstem to limbic structures and end up in the neocortex.
What gene mutation is associated with late onset PD?
LRRK2 - a cytoplasmic kinase so mutations increases kinase activity which leads to PD.
What proteins are associated with PD?
Mutations in genes that encode for the proteins DJ-1, PINK-1 and PARKIN.
How do PARKIN mutations cause PD?
Parkin is a ubiquitin E3 ligase.
It plays a crucial role in ubiquitination where molecules are covalently labelled with ubiquitin and directed towards degradation by proteasome or lysosomes.
Dysfunction in Parkin can lead to dysfunctional ubiquitinisation of dysfunctional molecules and they are then allowed to accumulate.
How do mutations in DJ-1 cause PD?
DJ-1 I s transcriptional regulator and has cytoprotective effects in mitochondria when they come under oxidative stress.
Mutations in DJ-1 cause pathological oxidative stress in mitochondria making them dysfunctional and also contributes to disrupted protein degradation by the proteasome.
How do mutations in PINK1 cause PD?
PINK1 is a kinase that localises to the outer membrane of dysfunctional mitochondria and phosphorylates Parkins (ubiquitin E3 ligases) targets substrates for proteasomal destruction.
If dysfunctional, dysfunctional proteins and mitochondria are not cleared and therefore accumulate.
PINK1 and PARKIN activity rely on each other so dysfunction of either will lead to dysfunctional mitochondrial accumulation.
Describe the morphology of PD.
Depigmentation of substantial nigra due to loss of dopaminergic neurons not producing dopamine which becomes oxidised to melanin.
Areas of neuronal loss show gliosis causing scars om the brain impacting function (too many or large glial cells to account for the loss of neurons).
Lewy bodies found in remaining neurons.
How is PD diagnosed?
No specific test for diagnosis.
Look for specific symptoms.
Triad of symptoms = bradykinesia, rigidity and tremor.
Additional symptoms may include postural instability, micrographia (small writing) and abnormal gait.
How can a PD diagnosis be best confirmed?
Sustained response to L-DOPA replacement therapy.
