Module IV - Lecture 6 - Parkinsons Disease

Question 1

What is the hallmark feature in PD?

Answer 1

bradykinesia - problems with initiating movement

Question 2

How is PD diagnosed?

Answer 2

-bradykinesia; rigidity or rest tremor
-clinical or imaging evidnece of alternate diagnoses of parkinsonism like atypical or drug induced or tremor
-L-DOPA responseiveness or dyskinesia

Question 3

What is L-DOPA?

Answer 3

precursor to dopamine production - slows PD progression or dopamine produced in the brain

Question 4

What are some other symptoms of PD?

Answer 4

anxiety
bladder issues
central pain
cognitive issues
constipation
depression
difficulty sleeping
fatigue
involuntary movement
loss of smell
muscle spasms
restlessness
sciatica
sexual dysfunction
skin cancer
slowed movement
speech changes ‘
stiff muscles

Question 5

What is the concordance rate of PD?

Answer 5

MZ and DZ twins have same concordance rate of 16-20% so genetic component but mostly environmental
young onset MZ>DZ

Question 6

What is the progression of PD symptoms?

Answer 6

prodromal - REM sleep disorder, depression, anxiety, hyposmia, constipation

early stage PD - bradykinesia, rigidity, tremor, mild cognitive impairment

mid stage PD - dyskinesia, hypotnetsion

late stage - PIGD, falls, dementia

have both motor and nonmotor symptoms

Question 7

What is the incidence rate of PD in men and women and when does this start?

Answer 7

it is the same
starts in the lat 40s

Question 8

Where do nuclei in the VTA project to?

Answer 8

nucleus accumbens and this is a dopamine mesolimbic pathway which is the reward pathway - these neurons are not affected by PD

Question 9

Where do DA neurons in the SN project to?

Answer 9

striatum and is important in initiation of movement and control this is what is affected

Question 10

PD arises from loss of function in what pathway?

Answer 10

nigrostriatal pathway- SN projects to GABA neurons in the striatum and the DA neurons die over time and get loss of function in the pathway

Question 11

In most cases of PD loss of nigrostriatal pathway function is due to what?

Answer 11

neuronal death preceded by lewy body formation

Question 12

What are lewy bodies and where do they form?

Answer 12

in somas of neurons of the SN
-come from alpha synuclein protein aggregates

Question 13

What kind of protein is alpha synuclein and how does this misfolding occur?

Answer 13

-is it an intrinsically unstructured protein has no tertiary structure which amkes it likely to misfold
-this misfolding causes misfolded protein to bind to other misfolded protein to stabilize and this form toxic oligomers

Question 14

What can the toxic oligomers from alpha synuclein misfolding cause?

Answer 14

loss of mitochindria and ATP generation loss and calcium inside mitochodnria burst open and causes an eznyme caspase to cause apoptosis

Question 15

When toxic oligomers and beta pleated sheets are released from the cell what can happen to them and what can they cause?

Answer 15

can be taken up by neihgboring cells and cause misfolding of neighboring alpha synucelin like a prion

Question 16

What are prions?

Answer 16

infections agents made of protein material that can fold in multiple ways and at least one of which is transmissible to other prior proteins

Question 17

What is the refolding model for a prion disease?

Answer 17

there are two structural states of a protein and most of the protein is folded right and then a gene in the protein causes it to misfold or exogenous material causes it to misfold and then it can bind to normal alpha synuclein and transform it into a misfolded alpha synuclein and then you can lewy bodies

Question 18

What is the seeding model for a prion disease?

Answer 18

the folded correctly and misfolded conformations of a protein are in equilibrium and the equilibrium shifts to more misfolded which then binds to each other and causes even more misfolding and then you get lewy bodies

Question 19

How was it experimentally examined if PD was a prion disease?

Answer 19

need to go take a brain extract from people with PD and have a nigrostriatal neurons which died and cultured heck cells with brain extract from PD patients GFP alpha synuclein and did not see a change in clustering but did for MS atrophy disorder
-did the same thing with cultured neurons and saw some aggregation of alpha synuclein when exposed to PD but way less than the MS atrophy one

Question 20

What is the circuit level dysfunction in PD?

Answer 20

-high levels of dopamine release inhibition of movement while low levels of dopamine occur in PD

Question 21

What does the basal ganglia which is the SNc and Striatium exert on motor systems?

Answer 21

constant inhibitory influence

Question 22

What is the normal D1 pathway?

Answer 22

SNc - dopamine (excite)—->D1 Striatum (inhibit) —–> GPi SNr (inhibit) ——->Thalamus(excite) ——> cortex

Question 23

What is the normal D2 pathway?

Answer 23

SNc - dopamine (inhibit)—->D2 Striatum (inhibit) —–> GPe(inhibit) ——->STN(excite) ——> GPi SNr(inhibit)—–> Thalamus (excite) —–> cortex

Question 24

In PD what happens to the D1 and D2 pathways?

Answer 24

less DA input from SNc to striatum

Question 25

What are the genetic causes of PD?

Answer 25

minority of cases come from a clear genetic cause
-aplha synucelin gene SNCA cope number variation in which you have two copies of alpha synuclein sio can get 3 or 4 coipies and way more of protein and get more misfolding and protein aggregation andthese people have child onset of PD
-can have missense mutations to and get more lewy body formation cause greater misfolding

Question 26

What does alpha synuclein do?

Answer 26

influence vesicle release of dopamine and are associated with synaptic vesicles and axons of DA neurons and they influence which vesicles fuse with plasma membrane

Question 27

What are the different synaptic vesicle release systems?

Answer 27

fuse and collapse - clathrin
kiss and run - fusion machinery
fuse pinch and linger - dynamin

Question 28

How was the role of alpha synuclein in vesicle fusion elucidated using pH sensitive fluorophore?

Answer 28

-inside vesicle is acidic pH 5 and outside is neutral - there are pH sensitive fluorophores in a synaptuc vesicle and when they are exposed to acidic molecules they flow and when they fuse with the membrane you get fluid contunuity and the fluorophore glow but then goes away once you fuse so can evalutae time coruse
-full decay - no fluorescence, spike, then no fluorescence
-plateau decay - fusion pore opens and then it is is open for sometime then collapses
-decay - plateau - decay happens and then a plateau
-plateua-decay-plateua - fuse small pore dumps some and then closes again and keeps some of it

alpha synuclein promotes full decay - over express protein more full decay KO protein less full decay

Question 29

What do PD mutations in alpha synucelin prevent?

Answer 29

rapid full fusion of synaptic vesicles
-the mutations prevent alpha synuclein from leaving the dendrites and making it out of the soma
-A30P alpha synuclein has less full decay

Question 30

What dysfunction contributes to PD symptoms?

Answer 30

circuit level dysfunction

Question 31

How is PD treated?

Answer 31

L-DOPA can cross BBB and dopamine cannot so it is given and L-tyrosine which is precursor gets transformed into L-DOPA via tyrosine hydroxylase and dopa decarboxylate makes it dopamine

Question 32

What does COMT do?

Answer 32

LDOPA breakdown into 3OM Dopa
-can give entacapone opicapone and tolcapone to inhibit this

Question 33

What does AADC do?

Answer 33

converts LDOPA to dopamine outside BBB

carbidopa prevents this

Question 34

What is MAOB?

Answer 34

breaks down dopamine in synaptic cleft - can prevent this

Question 35

What agonists can you give to prevent PD?

Answer 35

D1R and D2R agonists

Question 36

Is pharamcological boosting of dopamine a treatment or cure of PD?

Answer 36

only treatment