Case 7 - Parkinson's Pathophysiology

Question 1

where does PD firstly affect the brain

Answer 1

firstly affects the dorsal motor nucleus of the vagus nerve and the olfactory bulbs and nucleus

Question 2

where does it affect after this

Answer 2

the locus coerleus
then eventually the substantia nigra
cortical areas of the brain are affected at a later stage

Question 3

what happens to unused dopamine

Answer 3

is absorbed back into the presynaptic cell, once back in the cell, the excess dopamine is repackage into storage vesicles and released once more into the synapse

Question 4

what two enzymes break down dopamine

Answer 4

MAO - monoamine oxidasse
COMT - catechol-0-methyl transferase

Question 5

where is degeneration of dopamine neurones particularly evident

Answer 5

in a part of the substantia nigra called the pars compacta

Question 6

what does the loss of dopamine in the pars compacta do

Answer 6

increases the overall excitatory drive of the basal ganglia, disrupting voluntary motor control and causing the characteristic symptoms of PD

Question 7

what are Lewy bodies

Answer 7

are abnormal aggregates and inclusions of protein that develop inside nerve cells of people who have Parkinson’s

Question 8

what do the aggregations consist of

Answer 8

insoluble fibrillary aggregates containing misfolded proteins

Question 9

what is the main component of Lewy bodies

Answer 9

alpha synuclein

Question 10

what do these inclusions and aggregates likely symbolise

Answer 10

the end stage of a cascade of complicated events. an earlier stage may be more directly tied up to the pathogenesis of the disorder than the inclusions themselves, which may or may not represent diagnostic hallmarks

Question 11

what is Parkinsonism

Answer 11

a neurologic syndrome in which a patient exhibits dome of the symptoms associated with Parkinson’s disease, tremor, rigidity, bradykinesia and postural instability

Question 12

are Lewy bodies seen in Parkinsonism

Answer 12

no

Question 13

what is the largest nucleus of the basal ganglia

Answer 13

the striatum which consists of the caudate nucleus and the putamen

Question 14

what does the SNCA gene do

Answer 14

encodes the protein alpha-synuclein, the main components of Lewy bodies and the noted pathology marks in autopsy slides of PD brains

Question 15

what do mutations in the SNCA gene account for

Answer 15

about 2% of the familial cases, though not all persons with these changes have development PD

Question 16

how is SNCA transmitted

Answer 16

in a dominant fashion

Question 17

what does alpha synuclein also do

Answer 17

regulates the release of neurotransmitters at the presynaptic terminal. in addition, it seems to modulate intracellular dopamine concentration through interactions with proteins that regulate dopamine synthesis and uptake

Question 18

what is the PARK8 (LRRK2) gene

Answer 18

is a signalling protein that becomes toxic when it mutates

Question 19

what does the LRRK2 gene encode for

Answer 19

protein called dardarin

Question 20

what is the dardarin protein

Answer 20

one segment of the protein contains a large amount of an amino acid called leucine.

Question 21

what to proteins with leucine rich regions appear to do

Answer 21

play a role in activities that require interactions with other proteins such as transmitting signals or helping to assemble the cells structural cytoskeleton

Question 22

what are the recessive genes in PD

Answer 22

PARK2
PARK6 - PINK1
DJ-1 - PARK7

Question 23

what is the PARK2 - PARKIN gene

Answer 23

one of the largest human genes, provides instructions for making a protein called Parkin which plays a role in the breakdown of unneeded proteins

Question 24

how does it break down unneeded proteins

Answer 24

by tagging damaged and excess proteins with molecules called ubiquitin.

Question 25

what does ubiquitin serve as

Answer 25

a signal to move unneeded proteins into specialised cell structures known as proteasome, where the proteins are degraded

Question 26

what does the ubiquitin-proteasome system act as

Answer 26

the cells’ quality control by disposing of damaged, misshapen and excess proteins.

this system also regulates the availability of proteins that are involved in several critical cell activites, such as the timing of cell divisions and growth. because of its activity in the ubiquitin-proteasome system,Parkin belongs to a group of proteins

Question 27

what is the group of proteins that Parkin belongs to called

Answer 27

E3 ubiquitin ligases

Question 28

what else is Parkin involved in

Answer 28

the maintenance of mitochondria, the energy producing centres in cells

Question 29

what does PINK1 do

Answer 29

senses damaged mitochondria and recruits and activates Parkin to degrade and recycle damaged mitochondria.

Question 30

where are the loss of neurones in PD

Answer 30

the nigrostriatal dopaminergic neurones

Question 31

what happens when the compacta cells are destroyed in PD

Answer 31

the inhibitory outflow of the basal ganglia is abnormally high, and thalamic activation of upper motor neurones in the motor cortex is therefore less likely to occur

Question 32

what happens to the D1 receptors in PD

Answer 32

less activation - means that there will be a decrease in dynorphin, thus causing a decrease in the stimulation of the direct pathway

Question 33

what happens to the D2 receptor In PD

Answer 33

less activation which means there will be an increase in enkephalin, thus causing a decrease in the inhibition in the indirect pathway

Question 34

what do surviving neurones contain

Answer 34

aggregations of protein called Lewy bodies