PD II

Question 1

what are disease modifying strategies

Answer 1

interrupts the progression of the disease and does not tackle the pathogenesis

Question 2

2 types of disease modifying strategies

Answer 2

neuroprotective - preserves neurons/slows down degeneration

neurorepair - cell replacement, regeneration, or repair

Question 3

benefits of disease modifying treatment

Answer 3

-stabilises symptoms
-reduces large doses
-L-DOPA sparing - reduces risk of LID
-potentially repair existing damage to neurons

Question 4

multifactorial pathogenesis

Answer 4

1) neuroinflammation via microglia
2) excitotoxicity via intracellular Ca2+ rise
3) pacemaker channel CaV1.3
4) Impaired mitochondria releases cytochrome C
5) Neurotrophic factors GDNF
6) a-syn impacts mitochondrial dysfunction
7) increased LRRK2 activity phosphorylates a-syn

Question 5

what does activated microglia release

Answer 5

cytokines, interleukins-2B (TNF-a, IL-1B,IFN-7) activates innate immune system

a-syn triggers adaptive immune system

Question 6

what does innate and adaptive immune system activate

Answer 6

cell death pathways

Question 7

neuroinflammation strategies

Answer 7

NSAIDS not effective

azathioprine (immunosuppressant) used for Phase II trials

Exendin-4 (GLP-1 agonist)

Exenatide

Question 8

exendin-4

Answer 8

glucagon like peptide 1 receptor agonist
GLP-1 highly expressed in microglia
from lizard saliva

reduces microglia activation and inflammatory molecules (TNF-a, IL-1B)

Question 9

Kim et al., 2009 study

Answer 9

mice given ex-4 injections 30 mins prior to 4 MPTP injections

DA cells in SNc and striatal terminals spared
microglial activation (Iba1 marker) reduced

Question 10

Exenatide

Answer 10

synthetic 39aa peptide used for type 2 diabetes - reduced incidence of PD

decline in DAT (halts disease progression), exen group returns towards placebo group in washout means no protective effects

Question 11

2 routes of excitotoxicity

Answer 11

increased STN firing (indirect pathway) causes excitotoxic cell death via NMDAR activation and Ca2+ activation, SNc innervated by increased glutamate activation

voltage gated CaV1.3 pacemaker calcium channel in SNc increases calcium influx

Question 12

calbindin levels

Answer 12

SNc has reduced calbindin levels (binds to calcium) elevates calcium levels

Question 13

excitotoxicity therapies

Answer 13

riluzole activates GLT-1 (glutamate transporter to astrocytes) to increase glutamate reuptake

isradipine (l-type calcium channel blocker) anti-hypertensive

Question 14

potential targets for excitotoxicity

Answer 14

CaV1.3 antagonist

mGlu5 (post synaptic Gq coupled) antagonist

mGlu4 (pre synaptic Gi/Go)

Question 15

impaired mitochondrial activity in SNc

Answer 15

uncoupled ETC
electrons leak off respiratory chain
electrons combine with oxygen in mitochondria - Fenton reaction

30% less gluthathione in SNc (antioxidant)
Ox stress markers post-mortem
SN has higher ROS production due to H2O2 (bi product of DA auto oxidation)

Question 16

mitochondrial damage therapy

Answer 16

BIIB122 (DNL201) LRRK2 antagonist

reduces LRRK2 phosphorylation in PD and healthy patients

Question 17

what does loss of GDNF cause

Answer 17

dysregulation of RET receptor which GDNF signals from

Question 18

GDNF therapy

Answer 18

lentiviral vector infusion of GDNF into MPTP (bilateral parkinsonism)

striatal TH preserved, parkinsonism disability reduced, DA terminals preserved in striatum

Question 19

role of a-syn

Answer 19

neurotransmission
interact with SNARE to promote vesicle fusion

Question 20

how does a-syn protein accumulation occur

Answer 20

GBA1 mutant: inhibits autophagy

LRRK2 mutant: inhibits autophagy, mitochondrial function and proteasomal degradation

Question 21

location of a-syn oligomers

Answer 21

neurons - impair SNARE assembly complex, increase ROS, inhibit UPS and autophagy

mitochondria - inhibit protein import complex I, increase ROS, impair mitophagy

ER - ER stress, impairs protein folding

glia - reduce GDNF product

Question 22

6 ways to target a-syn

Answer 22

1) reduce SNCA mRNA expression - modulate histone deacetylase/RNAi

2) reduce transmission: block a-syn entry via LAG3 receptor Abs - only effective in cells

3) reduce aggregation/oligomerisation - use heat shock, Anle138b prevents oligomer formation

4) boosts autophagic/lysosomal clearance - Ambroxol (chaperone) delivers GCase to lysosomes. Tyrkinase inhibitor (Nilotinib) boosts autophagy

5) Immunotherapy - neutralises a-syn

6) probiotics

Question 23

how does ambroxol increase autophagy

Answer 23

increases GCase protein to promote a-syn clearance

ambroxol used in cough linctus to promote mucus clearance (repurposed drug)

Question 24

passive immunotherapy (uses antibodies)

Answer 24

cinepanemab (biogen) targets the N-terminal of aggregated a-syn

prasinezumab (roche) targets c-terminal of aggregated protein

Question 25

active immunotherapy uses truncated a-syn

Answer 25

affitope (austrian biotech) vaccine PDO1A
mimics 8 aa in c terminal of a-syn

Question 26

gut brain axis therapy

Answer 26

probiotic symprove

Question 27

2 types of considerations

Answer 27

clinical and pre-clinical

Question 28

clinical considerations

Answer 28

small participant group

washout insufficient to separate symbiotic and disease modifying effects

heterogeneous participants: varying DA depletion at start

UPDRS and imaging is expensive and time consuming

better to use intervention (biomarkers)

Question 29

pre-clinical considerations

Answer 29

lack of translational animal models since not all features of disease are replicated in rodent and primate models

toxin models (6-OHDA and MPTP) are rapid in onset with limited or no progression

degeneration limited to nigrostriatal pathway

transgenic rodent models have variable degeneration and phenotype

suggestion: use pre-formed a-syn fibril models

Question 30

2 methods of pre-clinical markers

Answer 30

olfactory dysfunction - PD patients experience pre-symptomatic hypoosmia - ties with early LB pathology
combine olfactory testing with DAT SPECT scans

biomarker (GCase levels in blood spots/CSF)

Question 31

PPMI

Answer 31

parkinson’s progression markers initiative