Lecture 22 - The Cellular and Genetic Basis of PD. Flashcards
Describe idiopathic PD.
Death of several neuron groups.
Degeneration of dopaminergic neurons in the SN gives rise to the motor features.
Presence of Lewy bodies - clumps of abnormal protein particles that accumulate in the brain.
What are some non-motor symptoms of PD?
REM sleep disorder
Altered sense of smell
Constipation
Autonomic failure
Psychosis
Dementia
Why is the SN of a PD patient depigmented?
SN is in the midbrain and cells produce dopamine.
With time dopamine oxidises to a brown pigment called melanin.
In PD there is depigmented SN as there is less dopamine.
Describe LDOPA as a treatment for PD.
LDOPA is a dopamine precursor that is converted into dopamine in dopaminergic neurons.
Remains the most effective oral medication for PD.
Can cause hallucination and delusions, OCD, mood swings, confusion, psychological changes, sleepiness and fainting.
Chronic use is associated with dyskinesia.
What are some causes of PD?
Build up of proteins - failed to be degraded by 26S protease.
Nueromelanin - dopamine when oxidised produces free radicals which are problems for cells.
Mitochondrial dysfunction.
Neuronal loss with ageing.
What environmental factors are linked to PD?
Rural living
Head trauma
Toxic exposure to things such as MPTP, herbicides and pesticides and solvents.
Infectious exposure.
What are good protective agents against PD?
Smoking
Drinking coffee
What is MPTP and how is it linked to PD?
A synthetic heroin that causes acute PD in users.
Selective chemical toxin that goes into the brain. MPP+ is a good substrate for dopamine transporters expressed by dopaminergic cells and goes into all dopamine producing cells in the brain.
MPP+ in the cell is a selective inhibitor of mitochondrial complex I resulting in a huge electron burst, going into the synapse and killing cells.
So, selective degeneration of SN.
Describe alpha synuclein in PD.
A normal protein found in most nerve cells involved in neurotransmitter vesicle recycling.
When it becomes abnormally folded and aggregates as Lewy bodies and Lewy neutrites in iPD.
Mutations are rare but cause a rapid course of disease (5 years instead o 10-20).
Point mutations in alpha synuclein protein causes the amino acids to change and there it accumulates in dopaminergic neurons.
Describe the role of proteosomal metabolism in PD.
This is key for removal of aged protein via the 26S proteasome.
Ubiquitin ligase take ubiquitin and detects whether the substrate is aged or dysfunctional or oxidised.
If it is it is put on ubiquitin chains which are recognised by the proteasome which can degrade the protein into amino acids or short peptide chains.
Mutations in this give rise to problems as the dysfunctional proteins are allowed to accumulate and form oligomers.
Describe the PARKIN gene.
Autosomal recessive mutations are loss of function mutations.
Early onset, slow progression, no Lewy bodies.
Acts as a ubiquitin E3 ligase.
Parkin -/- mice showed structurally normal mitochondria and no loss of dopaminergic neurons. Altered mitochondrial number, proteins and function and synaptic transmission impaired.
Describe PINK1.
Autosomal recessive.
28 pathogenic mutations discovered to date.
Typical PD phenotype with slow progression, Lewy bodies and a sustained response to LDOPA.
How do PARKIN and PINK1 interact at the mitochondrial membrane.
PINK1 localisation is in depolarised mitochondria.
PINK1 sits on the outer mitochondrial membrane and recruits PARKIN.
Recruitment of PARKIN relies on intact pINK1 activity.
Outer mitochondrial proteins are ubiquinated by PARKIN/PINK1 and mitochondria are then targeted for autophagy.
Describe DJ-1.
Autosomal recessive.
Earl onset, loss of function and point mutations.
No Lewy bodies.
DJ1 interacts with PARKIN and PINK1 and acts as a redox sensor, stabilising mitochondria under stress.
Describe LRRK2.
Most common form of early onset PD.
Autosomal dominant.
Rapid clinical progression with dementia.
Dual activity kinase and GTPase, autophagy, vesicle trafficking, mitochondrial outer membrane.
