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PD III Flashcards

1
Q

Why do we care about Lewy Bodies

A

They are a hallmark of PD

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2
Q

What are lewy bodies

A

Lewy bodies are cytoplasmic inclusions of misfolded proteins

They have a dense core surrounded by filamentous material

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3
Q

Lewy Body Makeup

A

Dense core made of : lipids, organelles, membranes intermingled with alpha-synuclein
The core is surrounded by filamentous material

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4
Q

Lewy bodies were described first in ____ as a major ________ of PD brains.

A

1902; pathological characteristic

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5
Q

Role of α-synuclein

A
  • Major constituent of Lewy bodies
  • First protein linked to familial PD (in 1997).
  • It is also directly implicated in susceptibility to idiopathic PD (i.e. also has a role in sporadic PD)
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6
Q

Lewy bodies spread from ____ but their role in ____ is still controversial

A

Lewy bodies spread from the brainstem to striatum and cortex (or even from the gut and nose to the brain!), but their role in disease pathogenesis is still controversial

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7
Q

How Lewy bodies spread

A

From gut via vagus nerve

and nose via glossopharyngeal nerve

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8
Q

T/F: Disease severity and duration correlate with the number of Lewy bodies

A

FALSE

Disease severity and duration DO NOT correlate with the number of Lewy bodies, but with the overall α-syn burden.

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9
Q

T/F Lewy bodies are seen in all PD

A

FALSE

Some familiar forms o PD (parkin- or LRRK2–parkinsonism) have no Lewy bodies.

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10
Q

Lewy bodies originate in ____ explaining these symptoms ______ of prodromal PD

A

Originate in nose and gut; explaining anosmia, constipation, sleep disorders seen in Stage I/prodromal PD

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11
Q

T/F: α-synuclein burden is directly linked with PD severity

A

TRUE

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12
Q

α-Synuclein is a ___ kDa _____ that can ______ and has ___ main domains

A

a-synuclein is a 15 kDa cytosolic protein that can associate to membranes and has three main domains:

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13
Q

3 domains of α-Synuclein

A

1) N-terminal Amphipathic region (membrane-binding domain)
2) centre hydrophobic region (NAC domain)
3) C-terminal acidic region (calcium-binding domain)

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14
Q

Membrane binding domain of α-Synuclein

A

2 alpha-helical structure seperated by a break KTEGV motif
On N-terminal end; amphipathic
Allows membrane binding

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15
Q

NAC domain of α-Synuclein

A

Center of protein
contains Serine 87
Promotes aggregation

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16
Q

Calcium-binding domain of α-Synuclein

A

C-terminal end; acidic
contains serine 129
C-terminal is acidic and unstructured –> has high (-) charge and may old to hydrophobic end in normal brains to prevent aggregation BUT in acidic conditions (i.e. in lysosomes) the negative charge may promote aggregation

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17
Q

C-terminus of α-Synuclein in normal vs. PD brains

A

C-terminal is acidic and unstructured –> has high (-) charge and may old to hydrophobic end in normal brains to prevent aggregation BUT in acidic conditions (i.e. in lysosomes) the negative charge may promote aggregation

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18
Q

Missense mutation in ____ domain is associated with ____ PD

A

membrane-binding domain (N-terminus); familial PD

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19
Q

α-Synuclein NORMAL function

A

highly enriched in presynaptic terminals, where it associates, in part, to synaptic vesicles, has roles in:

  • Regulation of formation of synaptic vesicles from endosomes,
  • exocytosis
  • regulation of neurotransmitter release
  • maturation of presynaptic vesicles
  • synaptic vesicle recycling.
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20
Q

In short, normally α-Synuclein has an important role in the _____

A

SYNAPSE (associates to synaptic vesicles)

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21
Q

Mutations of α-Synuclein linked to familial PD

A

• missense point mutations (autosomal dominant PD)
• gene duplication and triplication
• polymorphisms in the gene promoter that increase
transcriptional activity

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22
Q

Changes to α-Synuclein in idiopathic PD

A

In idiopathic PD, a-synuclein undergoes conformational changes, oligomerizes and/or forms protein aggregates (fibrils, Lewy bodies).
Some of these forms are toxic to neurons.

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23
Q

a-synuclein and disease spreading

A

Misfolded a-synuclein can be secreted by neurons and be transferred from neuron to neuron, thus spreading the disease

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24
Q

Loss of function effects of a-synuclein

A
  • impairs microtubule formation and axonal transport

- causes presynaptic dysfunction and abnormal NT release

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25
Gain of function effects of a-synuclein
- can form pores and leak NT from vesicles - causes mitchondiral dysfunction (increase OXI stress) - overwhelms Ca-buffering ability - ER stress - disrupts ER and golgi trafficking - impairs proteostasis including protein degradation by ubiquitin-proteasome and autophagy-lysosomal systems - promotes neuroinflammation (activates microglia)
26
Targeting α-Synuclein in PD DRUGS
- Clenbuterol --act on transcription - siRNA--degrade mRNA to prevent translation - HSPs and Anle138b -- prevent misfolding/block aggregation - Immunotherapy: AFFITOPE PD03A (active) or PRX002 (passive) --degrade extraceullar α-Syn - Ambroxol hydrochloride, autophagy activators --> dipsoe of α-Syn inside the cell
27
Targeting α-Syn (where can drugs act)
- production--lower α-Syn levels - aggregation--prevent misfolding or aggregation (prevent lewy body formation) - intracellular degradation - extracellular degradation - Uptake--reduce α-Syn uptake by neighbouring cells (prevent spread)
28
Ambroxol hydrochloride
Facilitate α-Syn degradation in lysosome (intracellular degradation)
29
Autophagy activators
Intracellular degradation of α-Syn
30
Clenbuterol
prevent α-Syn transcription (DNA --> mRNA) | block α-Syn production
31
siRNA
degrade mRNA to prevent translation of α-Syn | block α-Syn production
32
HSP, ANle138b
prevent misfolding/block aggregation and formation of Lewy bodies prevent aggregation
33
AFFITOPE PD03A (active) or PRX002 (passive)
Dispose of α-Syn outside of cell (extracellular degradation) | IMMUNIZATION AGAINST α-Syn
34
RNA interference (RNAi)
Strategy to reduce α-Synuclein | concern: decrease of α-syn could be deleterious
35
Why could a decrease of α-syn be deleterious
In rat and monkey models where α-syn was decreased by 90%, degeneration of the nigrostriatal pathway was observed α-syn is one of the most abundant proteins in the brain and is needed for normal functioning
36
β-2-adrenoreceptors and alpha-syn
Activation of β-2-adrenoreceptors (clembuterol, salbutamol) to reduce α-Synuclein
37
β-2-adrenoreceptors
- G-protein-coupled receptor activated by epinephrine - Agonists used for the treatment of asthma and cardiac failure - Antagonists used for the treatment of hypertension and arhitmia - receptors found in liver, cardiac myocytes, SM of blood vessels, pancreas--affect depends on tissue
38
Testing of FDA library compounds against PD
4 passed screening and 3 were beta-agonist and 2 can pass the BBB Metaproterenol (can't cross BBB), clenbuterol (BBB permeable), salbuterol (BBB permeable)
39
Clenbuterol vs saline in PD
Clenbuterol decreases neurodegeneration in a mouse model of PD Less DA with MPTP admin, but better preserved with clenbuterol admin
40
MPTP
induces a PD-like phenotype in animals
41
Norwegian study (beta blockers vs beta agonists)
- Risk of PD is lower in a Norwegian population taking high doses of Salbutamol (Beta-agonist) as treatment for asthma compared to the general population - Conversely, the risk of PD is higher in a population taking propanolol (beta-blocker)
42
Drugs that reduce α-Synuclein in PD
- RNA interference (RNAi) | - Activation of β-2-adrenoreceptors (clembuterol, salbutamol)
43
Drugs that target α-Synuclein aggregation
- Drugs that increase production of Heat Shock Proteins | - Anle128b
44
Anle128b
- small molecule “modulator” of α-syn aggregation. - Protective in animal models of PD and tauopathies. - Still in pre-clinical development.
45
Anle128b---why use it
- bioavailable, crosses the BBB - low toxicity - ameliorates motor deficits in mice
46
Anle128b FUNCTION
- functions by preventing the formation of more toxic oligomers - shifts toward less toxic, disordered oligomers (vs, more toxic extended and partially disordered aggregate conformations)
47
Anle128b discovery as PD drug
found through high-throughput screening of thousands of compounds
48
Drugs that promote the degradation of α-Synuclein aggregates
- Drugs that increase autophagic-lysosomal degradation of α-syn - Ambroxol
49
Ambroxol: what is it
- FDA-approved mucolytic (mucous clearant) - It promotes folding and stabilization of of the lysosomal enzyme glucocerebrosidase (GBA), as well as its enrichment in the lysosomes, and promotes α-syn degradation. - basically unorives degration in lysosome
50
Ambroxol: stage of drug development
Two Phase II clinical trials with ambroxol are testing safety, tolerability and efficacy of the drug.
51
Glucocerebrosidase (aka: GBA, GCase)
- a lysosomal enzyme | - GB1 gene encodes for GBA
52
GB1
- encodes for GBA - Mutations result in Gaucher disease, a lysosomal storage disease (in homozygous patients) - Heterozygous carriers of GBA1 mutations have a 20-30 fold increased risk to develop PD. - 7-10% of PD patients carry mutations in this gene.
53
Relationship between GBA and α-syn
- Increased GBA activity = decreased levels of α-syn and aggregates (and therefore decreased toxicity) - And decreased GBA = increased α-syn
54
decreased GBA (aka GCase)
increased alpha-synuclein --> α-syn overexpression cells, PD triplication cels, PD brian--> cycles to decrease GBA --> worsens PD (by increasing α-syn)
55
How α-syn affects GBA (cyclic)
α-syn impairs normal GBA trafficking from ER (where it is translated) --> prevent protein maturation + localization into lysosomes --> decreased GBA in lysosomes --> glucoceramide (Glc Cer) accumulates --> stabilizes α-syn oligomers and promotes α-syn fibrilation --> some of these oligomers escape the lysosome --> cycles AMBROXOL can prevent this
56
Immunotherapy against α-syn
- Passive immunotherapy: PRX002 | - Active immunotherapy: AFFITOPE PD03A
57
HOW: Immunotherapy against α-syn
- Passive and active immunotherapies have been experimented in animal PD models with success (decreased central levels of α-syn, reduction of symptoms and lack of toxicity).
58
Potential concerns related to immunotherapy
- limited penetration of antibodies into the CNS - potential off-target responses and inflammatory reactions
59
Passive immunotherapy: PRX002
- Humanized antibodies against αsyn. It decreases plasma levels of α-syn by >90%. - CNS penetration demonstrated in Phase I trial (but may not pass through in large amounts) - Currently in Phase II trial
60
Active immunotherapy: AFFITOPE PD03A
- Vaccine containing α-syn synthetic peptide. - In Phase I clinical trial in a small number of PD patients - create anti-α-syn antibodies
61
PRX002 CNS penetration
CNS penetration demonstrated in Phase I trial BUT may not pass through in large amounts --> not a super-strong decrease in α-syn --> good because α-syn is important and don't want to completely deprive it
62
Glial-derived neurotrophic factor (GDNF)
- promote the survival of DA neurons | - In PD animal models, GDNF was shown to be neuroprotective
63
Glial-derived neurotrophic factor (GDNF) HOW
- Dimeric GDNF interacts with two molecules of GDNF family receptor α (GFRα1) co-receptor - The complex recruits the Ret receptor tyrosine kinase, promotes its dimerization and downstream signalling - GDNF-mediated signalling regulates various cellular functions, including survival and adhesion, it decreases DAT activity and promotes dopamine release - Severe neurodegeneration in the substancia nigra occurs when GDNF is reduced by 60% in animal models
64
GDNF has a role in promoting ___ release by ____
- DA release - decrease DAT activity (increase striatal DA) - increased phosphorylation of TH (first enzyme in DA synth) --> activate TH and therefore activates DA synth
65
Failure of GDNF in clinical trials--background
Open-label trials that administered GDNF into the putamen reported improvement of symptoms BUT A larger double-blind study showed no improvement
66
Failure of GDNF in clinical trials WHY
Potential reasons for trial failure - development of anti-GDNF antibodies - accumulation of α-synuclein in PD neurons disrupts GDNF signaling (Decressac et al, 2012) - Decreased levels of gangliosides in PD neurons disrupts GDNF signaling (Hadaczek et al., 2015)

PMCOL 412 (35 decks)

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