PD II Flashcards
Therapies
what are disease modifying strategies
interrupts the progression of the disease and does not tackle the pathogenesis
2 types of disease modifying strategies
neuroprotective - preserves neurons/slows down degeneration
neurorepair - cell replacement, regeneration, or repair
benefits of disease modifying treatment
-stabilises symptoms
-reduces large doses
-L-DOPA sparing - reduces risk of LID
-potentially repair existing damage to neurons
multifactorial pathogenesis
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
what does activated microglia release
cytokines, interleukins-2B (TNF-a, IL-1B,IFN-7) activates innate immune system
a-syn triggers adaptive immune system
what does innate and adaptive immune system activate
cell death pathways
neuroinflammation strategies
NSAIDS not effective
azathioprine (immunosuppressant) used for Phase II trials
Exendin-4 (GLP-1 agonist)
Exenatide
exendin-4
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)
Kim et al., 2009 study
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
Exenatide
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
2 routes of excitotoxicity
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
calbindin levels
SNc has reduced calbindin levels (binds to calcium) elevates calcium levels
excitotoxicity therapies
riluzole activates GLT-1 (glutamate transporter to astrocytes) to increase glutamate reuptake
isradipine (l-type calcium channel blocker) anti-hypertensive
potential targets for excitotoxicity
CaV1.3 antagonist
mGlu5 (post synaptic Gq coupled) antagonist
mGlu4 (pre synaptic Gi/Go)
impaired mitochondrial activity in SNc
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)
mitochondrial damage therapy
BIIB122 (DNL201) LRRK2 antagonist
reduces LRRK2 phosphorylation in PD and healthy patients
what does loss of GDNF cause
dysregulation of RET receptor which GDNF signals from
GDNF therapy
lentiviral vector infusion of GDNF into MPTP (bilateral parkinsonism)
striatal TH preserved, parkinsonism disability reduced, DA terminals preserved in striatum
role of a-syn
neurotransmission
interact with SNARE to promote vesicle fusion
how does a-syn protein accumulation occur
GBA1 mutant: inhibits autophagy
LRRK2 mutant: inhibits autophagy, mitochondrial function and proteasomal degradation
location of a-syn oligomers
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
6 ways to target a-syn
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
how does ambroxol increase autophagy
increases GCase protein to promote a-syn clearance
ambroxol used in cough linctus to promote mucus clearance (repurposed drug)
passive immunotherapy (uses antibodies)
cinepanemab (biogen) targets the N-terminal of aggregated a-syn
prasinezumab (roche) targets c-terminal of aggregated protein
active immunotherapy uses truncated a-syn
affitope (austrian biotech) vaccine PDO1A
mimics 8 aa in c terminal of a-syn
gut brain axis therapy
probiotic symprove
2 types of considerations
clinical and pre-clinical
clinical considerations
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)
pre-clinical considerations
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
2 methods of pre-clinical markers
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)
PPMI
parkinson’s progression markers initiative
