Parkinson's Disease

Question 1

What is parkinson’s disease?

Answer 1

neurodegenerative movement disorder, predominantly of old age
Often sporadic /idiopathic

Question 2

Describe the clinical presentation of parkinsons

Answer 2

Resting tremor
Akinesia - loss of power of voluntary movement
Bradykinesia - slowness of execution of movement
Dementia in later stages
Psychiatric symptoms - depression and anxiety

Question 3

Describe the epidemiology of parkinsons

Answer 3

1-2% of the population over the age of 65 have PD

Increases to 3-5% over the age of 85

Cause of death usually linked to incapacitation

Question 4

What are the two key pathological hallmarks of parkinsons?

Answer 4

1. Loss of neurons, predominantly dopaminergic and in the Substantia nigra
2. The accumulation of intracellular inclusions, called Lewy bodies, made up of the protein alpha synuclein

Question 5

What research did Arvid Carlson find out?

Answer 5

Carried out studies in rabbits showing that depletion of dopamine was critical for control of movement, and that it acted as a neurotransmitter in the substantia nigra

Subsequent studies revealed decreased dopamine levels in the basal ganglia of PD patients

Question 6

What are the environmental factors that are linked to parkinsons?

Answer 6

Pesticide exposure
MPTP (street/drug/meth?) exposure

Also exposure to influenza and repeated head trauma

Question 7

What is MPTP?

Answer 7

Identified in Californian drug addicts who used a ‘synthetic heroin’
contaminated with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine

The toxic species is MPP+ which enters mitochondria in neurons

Question 8

What are the genetic factors linked to parkinsons?

Answer 8

Inherited forms of Parkinson’s disease (familial parkinson’s)
Genetic susceptibility in sporadic Parkinson’s disease

Question 9

Give an example of a gene observed in familial parkinsons

Answer 9

LRRK2 gene

Question 10

What are some of the gene that cause Parkinson’s (7)

Answer 10

VPS35
PARK7
SNCA
LRRK2
PARK2
PINK1
ATP13A2

Question 11

What are the two key insights from genetics and toxin research?

Answer 11

Mitochondrial biology

Protein aggregation

Question 12

What causes mitophagy? Degradation of mitochondria

Answer 12

Factors such as oxidative stress, aging, pesticides

Genes such as Parkin
Fbxo7 and PINK1

Question 13

What was found regarding Protein aggregation that is linked to familial parkinsons disease?

Answer 13

Identification of mutations in alpha synuclein - quickly followed by the realisation that Lewy bodies were made up of this protein

Alpha synuclein readily aggregates and forms toxic lumps of sticky protein (amyloid) similar to that found in Alzheimer’s

Question 14

What is the currnt hypothesis about alpha cynuclein causing parkinsons?

Answer 14

Current hypothesis is that small aggregates of synuclein (oligomers) can spread from cell to cell, and cause cell death

May be analogous to prion diseases such as BSE (Mad Cow disease) and CJD (Creutzfeldt–Jakob disease)

Question 15

Describe the Dopamine pathway treatment?

Answer 15

Natural DA precursor which, unlike DA, can cross BBB.

L-DOPA is converted to dopamine by DOPA decarboxylase (DCC).

BUT L-DOPA is ~90% converted by DDC in intestinal wall
Given with peripherally-acting DDC inhibitors, carbidopa or benserazide

L-DOPA also ~5% metabolised by plasma Catechol O-Methyl Transferase
COMT inhibitor, entacapone, may be used as adjunct

Ensure majority of L-DOPA enters brain unchanged for conversion to DA
L-DOPA raises striatal DA levels to normalise activity in BG circuits

Question 16

What is an acute and chronic side effect of dopamine treatment?

Answer 16

Acute: psychosis
Chronic: excess movements (dyskinesia)

Question 17

L-dopa used as the first drug and most effective at symptom relief
What are some common preparations?

Answer 17

carbidopa/levodopa (co-careldopa) (e.g. Sinemet, Parcopa, duodopa)

benserazide/levodopa (co-beneldopa) (e.g. Madopar)

carbidopa, levodopa and entacapone (Stalevo)

Question 18

Describe the surgical intervention that can take place

Answer 18

Targeted lesion of subthalamic nucleus and globus pallidus brain areas
Decreases neuronal activity that is raised due to loss of signal from the substantia nigra
Destructive lesions are associated with significant side effects (neurologic deficits)
Deep brain stimulation using implanted electrodes in these brain regions increasingly being used as an alternative

Question 19

How can stem cell therapy be used? What issues are there?

Answer 19

• Replacement of cells in the basal ganglia to correct the underlying cause of lowered dopamine levels

Procedures carried out in Sweden (illegal in the US) with moderate success

Subsequent studies with sporadic PD patients have proved less successful, with some severe reactions to stem cell implantation

Key question is what cells to use: initial studies used fetal brain cells (from aborted embryos), more recently embryonic stem cells and induced pluripotent cells have been suggested as alternatives