Parkinson's Disease

Question 1

What are the clinical features of PD?

Answer 1

Characterised by:
= muscle stiffness (rigidity)
= slowness of movement (bradykinesia)
= tremor at rest
= poverty of movement (akinesia)

Also:
= postural deficits
= impaired gait
= short shuffling steps
= mask-like face
= cramped handwriting (micrographia)
= in later stages sometime dementia

Question 2

What are the main pathological features of PD?

Answer 2

Degeneration of dopaminergic (DA) neurons in substantia nigra pars compacta

Loss of DA in the caudate-putamen

Lewy bodies (intracellular)
= small, circular bodies located in cell body and axons of neurons in basal ganglia
= composed of α-synuclein protein

Question 3

Parkinson’s Disease Dementia (PDD) vs Dementia with Lewy Bodies (DLB) ?

Answer 3

Lewy body dementia
= broad term for both PDD and DLB
= have shared clinical symptoms

DLB = 3rd most common form of dementia
= also has accumulation of lewy bodies
(but in cortex and basasl ganglia)
= BUT different to PDD

Shared clinical symptoms of AD and PD
= hallucinations, disturbed sleep

DLB
= if cognitive symptoms appear same time / year before onset of motor problems

PDD
= if movement disorder diagnosed year before cognitive symptoms

Question 4

Summarise the different neuronal firings?

Answer 4

Excitation
= if neuron A fires, neuron B more likely to fire

Inhibition
= if neuron A fires, neuron B less likely to fire

Disinhibition
= if neuron A stops firing, neuron B more likely to fire

Question 5

What are the 2 motor circuits of the basal ganglia? What neurotransmitters are involved?

Answer 5

Direct

Indirect (contains Subthalamic nucleus)

Glutamate = excitatory
GABA = inhibitory
Dopamine 1 = excitatory
Dopamine 2 = inhibitory

Question 6

How do the motor circuits normally work?

Answer 6

DIRECT
= (glutamate) excites Caudate putamen
= which inhibits Globus pallidus (GABA) + Substantia nigra (GABA)
= which excites caudate putamen (D1) + inhibits thalamus (GABA)
= which excites motor cortex (through disinhibition) movement (Glutamate)
= INCREASED MOVEMENT

INDIRECT
= (glutamate) excites Caudate putamen
= which inhibits Globus pallidus (GABA)
= which inhibits Globus pallidus (internal GABA loop) + inhibits (GABA) Subthalamic nucleus + inhibits Thalamus (GABA)
= which excites Globus pallidus (glutamate) + excites Substantia nigra (glutamate)
= which inhibits caudate putamen (D2) + inhibits thalamus (GABA)
= which excites (glutamate) motor cortex (LESS)
= DECREASED MOVEMENT

= they balance each other out

Question 7

What happens to the motor circuits of the basal ganglia during Parkinson’s disease?

Answer 7

= overacting of the indirect pathway due to loss of dopamine (which acts as regulator)

= dopamine = action is to increase motor movement

= loss of dopamine = DECREASED movement

Question 8

What are some non-modifiable risk factors for PD?

Answer 8

Age
= mean onset age is 65

Sex
= higher in males (1.5:1)

Genetics
= 10% of cases due to mutation in genes:
(α-synuclein, UCH-L1, LRKK2, Parkin, DJ-1, PINK-1)

Question 9

What are the genetics of PD?

Answer 9

Genes involved in familial cases focus on:

1. Aggregation of α-synuclein
2. Protein recycling, degradation and repair (proteasome)
3. Mitochondria, free radicals, oxidative stress

(pathways may interconnect - causing nigral cell death)

Question 10

What are some α-synuclein mutations?

Answer 10

6 missense mutations (familial PD)
= A30P, E46K, H50Q, G51D, A53T/E

Mutations / overproduction of WT protein
= influences formation of toxic α-synuclein aggregates

H50Q
= may influence metal binding
= Cu2+ induces aggregation

NAC (non-amyloid domain)
= associated with increased fibril formation

Question 11

LRRK2 mutations?

Answer 11

LRRK2 (dardarin) = leucine-rich repeat kinase 2

= contains five consecutive domains of leucine-rich repeats

= small number of mutations found
(e.g. G2019S - autosomal dominant PD in caucasians)

Anti-LRRK2
= antibodies strongly label brainstem and cortical lewy bodies

Could play role in α-synuclein aggregation and lewy body formation

Question 12

Parkin and UCH-L1?

Answer 12

Abnormal proteins tagged with ubiquitin molecules for degradation by 26S proteosome complex

Polyubiquitin chains broken down and recycled

PARKIN
= part of ubiquitin E3 ligase complex
= mutations lead to AR-JP

UCH-L1
= ubiquitin carboxy-terminal hydrolase L1
= a de-ubiquitinating enzyme
= point mutation causes late-onset PD

UPS dysfunction
= build up aggregating proteins , clog up proteasome = vicious cycle

Question 13

DJ-1 and PINK1?

Answer 13

= both cause early-onset recessive PD

DJ-1
= mitochondrial protein
= acts as sensor for oxidative stress
= coded for by PARK7 gene
= deletion mutation, point mutation = parkinsonian features

PINK1
= PTEN-induced putative kinase 1
= mitochondrial serine/threonine- protein kinase that protects cell from stress-induced mitochondrial dysfunction
= over 70 mutations in gene found
= agreed with hypothesis that mitochondrial dysfunction + oxidative damage contributes to pathogenesis of PD

Question 14

What are some modifiable risk factors for PD?

Answer 14

Increased risk
= traumatic brain injury
= industrial exposure
= heavy metals (e.g. manganese, lead, copper)
= pesticides (e.g. rotenone, paraquat)
= obstructive sleep apnea

(EXTRA READING)
Possible decreased risk:
= smoking
= caffeine

Question 15

MPTP and Parkinsonism?

Answer 15

7 young people developed irreversible parkinsonism
= injected synthetic heroin containing MPTP

MPTP
= crosses BBB
= converted MPP+ (via MPDP+) by glial cells containing MAO-B
= MPP+ transported into dopaminergic neurons
= impairs electron transport in mitochondria = cellular damage / death

Question 16

MPP+ and pesticides?

Answer 16

MPP+ structurally similar to pesticide: paraquat

Rotenone + maneb = similar activity to MPP+

= inhibit mitochondrial complex 1
(NADH dehydrogenase)

= targets dopaminergic neurons

= can increase risk of PD

Question 17

BMAA in Guam?

Answer 17

= ALS-PD-Dementia complex of Guam

Due to BMAA in flour from cycad palm nuts
= glutamate agonist (due to similar structure)
= excitotoxicity and neurodegeneration
= causes high Ca2+ influx
= can NOT be regulated = neuron death

(also found in flying foxes that eat the nuts)

Question 18

Post-encephalic Parkinson’s ?

Answer 18

= outbreak of encephalitis lethargica (1915-1926)

= 50% of survivors developed parkinsonism

(EXTRA READING)
= post-encephalic = after brain injury or damage
= onset of symptoms more sudden
= cause is often unknown (idiopathic)

Question 19

Current treatments for PD?

Answer 19

Symptoms alleviated with L-dopa
= transported to brain + converted to dopamine
= administered with peripherally active Dopa decarboxylase inhibibitor (carbidopa)
= prevents premature conversion of L-dopa to dopamine

Inhibitors of COMT and MAO-B
= inhibit dopamine degradation

Sometimes dopamine agonists
= delays use of L-dopa
= L-dopa wears off after approx. 5 years

Surgery
= deep brain stimulation
= ?bypass substantial nigra?

(EXTRA READING)
Deep brain stimulation
=neurostimilator placed under chest, wires connected to subthalamic nucleus / globus pallidus
= electrical impulses supplied
= can drastically improve symptoms

Lesioning procedures
= destruction of small areas of brain often using heat
= can target specific areas of brain
= techniques include: radiofrequency lesioning, stereotactic radiosurgery, focused ultrasound

Question 20

What is in the PD treatment pipeline?

Answer 20

α-synuclein

antioxidants

botanicals

cell therapy

DA + non-DA symptom relief

energy + mitochondria

GBA (glucocerebrosidae)

metabolism (e.g. GLP-1)

immunotherapy (e.g. antibodies targeting α-synuclein)

kinase inhibitors

microbiome

(EXTRA READING)
= gene therapy
(to protect dopamine-producing neurons / increase dopamine production in the brain)

= stem cell therapy
(use stem cells that have ability to replace damaged or lost dopamine producing neurons)