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PMCOL 412 > PD III > Flashcards

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
Q

Gain of function effects of a-synuclein

A
  • 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)
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26
Q

Targeting α-Synuclein in PD DRUGS

A
  • 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
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27
Q

Targeting α-Syn (where can drugs act)

A
  • 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
Q

Ambroxol hydrochloride

A

Facilitate α-Syn degradation in lysosome (intracellular degradation)

29
Q

Autophagy activators

A

Intracellular degradation of α-Syn

30
Q

Clenbuterol

A

prevent α-Syn transcription (DNA –> mRNA)

block α-Syn production

31
Q

siRNA

A

degrade mRNA to prevent translation of α-Syn

block α-Syn production

32
Q

HSP, ANle138b

A

prevent misfolding/block aggregation and formation of Lewy bodies
prevent aggregation

33
Q

AFFITOPE PD03A (active) or PRX002 (passive)

A

Dispose of α-Syn outside of cell (extracellular degradation)

IMMUNIZATION AGAINST α-Syn

34
Q

RNA interference (RNAi)

A

Strategy to reduce α-Synuclein

concern: decrease of α-syn could be deleterious

35
Q

Why could a decrease of α-syn be deleterious

A

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
Q

β-2-adrenoreceptors and alpha-syn

A

Activation of β-2-adrenoreceptors (clembuterol, salbutamol) to reduce α-Synuclein

37
Q

β-2-adrenoreceptors

A
  • 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
Q

Testing of FDA library compounds against PD

A

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
Q

Clenbuterol vs saline in PD

A

Clenbuterol decreases neurodegeneration in a mouse model of PD
Less DA with MPTP admin, but better preserved with clenbuterol admin

40
Q

MPTP

A

induces a PD-like phenotype in animals

41
Q

Norwegian study (beta blockers vs beta agonists)

A
  • 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
Q

Drugs that reduce α-Synuclein in PD

A
  • RNA interference (RNAi)

- Activation of β-2-adrenoreceptors (clembuterol, salbutamol)

43
Q

Drugs that target α-Synuclein aggregation

A
  • Drugs that increase production of Heat Shock Proteins

- Anle128b

44
Q

Anle128b

A
  • small molecule “modulator” of α-syn aggregation.
  • Protective in animal models of PD and tauopathies.
  • Still in pre-clinical development.
45
Q

Anle128b—why use it

A
  • bioavailable, crosses the BBB
  • low toxicity
  • ameliorates motor deficits in mice
46
Q

Anle128b FUNCTION

A
  • 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
Q

Anle128b discovery as PD drug

A

found through high-throughput screening of thousands of compounds

48
Q

Drugs that promote the degradation of α-Synuclein aggregates

A
  • Drugs that increase autophagic-lysosomal degradation of α-syn
  • Ambroxol
49
Q

Ambroxol: what is it

A
  • 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
Q

Ambroxol: stage of drug development

A

Two Phase II clinical trials with ambroxol are testing safety, tolerability and efficacy of the drug.

51
Q

Glucocerebrosidase (aka: GBA, GCase)

A
  • a lysosomal enzyme

- GB1 gene encodes for GBA

52
Q

GB1

A
  • 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
Q

Relationship between GBA and α-syn

A
  • Increased GBA activity = decreased levels of α-syn and aggregates (and therefore decreased toxicity)
  • And decreased GBA = increased α-syn
54
Q

decreased GBA (aka GCase)

A

increased alpha-synuclein –> α-syn overexpression cells, PD triplication cels, PD brian–> cycles to decrease GBA –> worsens PD (by increasing α-syn)

55
Q

How α-syn affects GBA (cyclic)

A

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
Q

Immunotherapy against α-syn

A
  • Passive immunotherapy: PRX002

- Active immunotherapy: AFFITOPE PD03A

57
Q

HOW: Immunotherapy against α-syn

A
  • 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
Q

Potential concerns related to immunotherapy

A
  • limited penetration of antibodies into the CNS
  • potential off-target responses and inflammatory
    reactions
59
Q

Passive immunotherapy: PRX002

A
  • 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
Q

Active immunotherapy: AFFITOPE PD03A

A
  • Vaccine containing α-syn synthetic peptide.
  • In Phase I clinical trial in a small number of PD patients
  • create anti-α-syn antibodies
61
Q

PRX002 CNS penetration

A

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
Q

Glial-derived neurotrophic factor (GDNF)

A
  • promote the survival of DA neurons

- In PD animal models, GDNF was shown to be neuroprotective

63
Q

Glial-derived neurotrophic factor (GDNF) HOW

A
  • 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
Q

GDNF has a role in promoting ___ release by ____

A
  • 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
Q

Failure of GDNF in clinical trials–background

A

Open-label trials that administered GDNF into the putamen reported improvement of symptoms BUT
A larger double-blind study showed no improvement

66
Q

Failure of GDNF in clinical trials WHY

A

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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