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Molecular Neuroscience II > 14 - Parkinson's Disease > Flashcards

14 - Parkinson's Disease Flashcards

Stopped at page 10 (dysfunction of chaperon-mediated autophagy) UCHL1?

1
Q

Who described the ‘shaking palsy’ in 1817?

A

James Parkinson

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2
Q

What percent of the popilation over the age of 65 years has Parkinson’s disease (PD)?

A

1-2%

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3
Q

What is the most common neurodegenerative movement disorder?

A

Parkinson’s Disease

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4
Q

What are the motor symptoms of Parkinson’s Disease? (6)

A
  • Visible tremor (4-6 Hz present in hands and limbs of patients at rest)
  • Cogwheel rigidity (ratchet like muscle movements)
  • Bradykinesia (slowness of movement and reflexes)
  • Postural instability (impaired balance and coordination)
  • Change in gait (shuffling steps)
  • Dyskinesia from levodopa treatment (involuntary movement)
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5
Q

What are some non-motor symptoms of Parkinson’s Disease? (15)

A
  • Depression
  • Cognitive impairment
  • Psychosis
  • Hallucinations
  • Compulsive behaviour
  • REM sleep behaviour disorders
  • Excessive daytime somnolence
  • Orthostatic hypotension
  • Gastrointestinal symptoms
  • Constipation
  • Urinary and sexual dysfunction
  • Speech changes
  • Skin problems
  • Pain
  • Difficulty chewing and swallowing
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6
Q

What is the pathology observed in Parkinson’s Disease patients?

A
  • Loss of substantia nigra pars compacta (SNpc) dopamine neurons, in consequence, lower dopamine production.
  • Development of intracytoplasmic inclusions called Lewy bodies
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7
Q

What are Lewy bodies? Where are they found and what are they mode of?

A

Intracytoplasmic inclusions which mostly contain ubiquitin and α-synuclein

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8
Q

What are four risk factor for developing Parkinson’s disease?

A
  • Age
  • Heredity
  • Sex (more men than women)
  • Toxins (especially pesticides like MPTP and paraquat)
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9
Q

What three activities can offer neuroprotection against Parkinson’s disease?

What two N-methylated peptides inhibit the formation of α-synuclein aggregates?

A
  • Drinking coffee
  • Smoking tobacco
  • Taking nonsteroidal drugs (aspirin, tylenol)

These reduce the risk for PD and in vitro models show formation of α-synuclein aggregates was inhibited by N-methylated peptides, rifampicin and curcumin

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10
Q

Why do late onset Parkinson’s disease patients show earlier observed symptoms of dementia than patients with early onset PD?

A

Because of the coexistance of PD and AD in the late-onset of Parkinson’s Disease.

This is evidenced by more Lewy bodies in late onset with other age related pathologies (eg. cortical plaques made of Aβ and neurofibrillary tangles).

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11
Q

Why does Parkinson’s disease selectively affect dopamine neurons? (4)

A
  • Dopamine metabolism produces highly reactive species that oxidize lipids and proteins, increase oxidative stress and impair mitochondrial function.
  • Dopamine easily auto-oxidizes at neutral pH (cytosol), but is stable in low pH synaptic vesicles. Any process that prevents sequestering of DA into vesicles can cause DA oxidation and neurotoxicity
  • DA toxicitiy in the substantia nigra is reduced in α-synuclein-knockout mice. And DA and L-DOPA were shown to inhibit α-synuclein aggregation, which indicates important interactions between these substances on the cell survival/death mechanisms
  • DA is a precursor of neuromelanin, which is important for iron storage.
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12
Q

What do α-synuclein-knockout mice show?

A

Reduced DA toxicity in the substantia nigra

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13
Q

What can an imbalance in neuromelanin cause?

A

The imbalance of neuromelanin can trigger neurodegeneration and inflammatory processes

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14
Q

List the genes involved in Parkinson’s Disease

A
  • SNCA (α-synuclein)
  • LRRK2 (leucine-rich repeat kinase 2)
  • Parkin
  • UCHL1 (ubiquitin carboxyl-terminal esterase L1)
  • PTEN (phosphatase and tensin homolog
  • PINK1 (phosphatase and tensin homolog (PTEN)-induced kinase 1)
  • DJ-1
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15
Q

Describe what happens with mutations in the α-synuclein (SNCA) gene (3)

A
  • Rarely causing of familial Parkinson’s disease
  • Enhanced expression of WT non-mutated α-synuclein plays an important role in the development of sporadic PD
  • Main neuropathological changes observed in PD are lewy bodies and Lewy neurites made of fibrillar forms of α-synuclein protein
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16
Q

What is α-synuclein protein?

A

A small, 140 amino acid protein, concentrated in the neuronal synaptic terminals. Function of α-synuclein is unclear, but some data indicates involvement in vesicle trafficking and mitochondrial transport

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17
Q

Describe what happens with mutations in the LRRK2 (leucine-rich repeat kinase 2) gene? (2)

A
  • The most common cause of late onset familial Parkinson’s disease
  • LRRK2 interacts with Parkin (component of ubiquitin ligase), which results in decreased ubiquitin-proteasome function
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18
Q

Where is the Parkinson’s disease associated LRRK2 (leucine rich repeat kinase 2) gene most expressed in the mammalian brain? (4)

A
  • Cerebral cortex
  • Striatum
  • Hippocampus
  • Lower level in the substantia nigra
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19
Q

What is the Parkin gene connected with?

A
  • Autosomal recessive juvenile Parkinson’s disease, which is characterized by DA neurons degenerating without formation of Lewy bodies
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20
Q

What do mutations in the DJ-1 gene cause?

A

Rare autosomal recessive early onset Parkinson’s disease

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21
Q

Most of the genes involved in the pathogenesis of Parkinson’s disease encode proteins for _____ or ____?

A
  • Important for either mitochondrial physiology
    or
  • Ubiquitin-proteasome protein degradation

Can see slide 8 of Parkinson’s disease presentation for clarification.

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22
Q

Describe the mitochondrial pathology induced by aberrant α-synuclein and LRRK2

A
  • Increased mitochondrial levels of α-synuclein in PD have been associated with reduced complex I (NADH dehydrogenase) activity, and in consequence, with oxidative stress
  • α-synuclein is required for MPP+ -induced activation of nitric oxide synthase (NOS) and the cytosolic accumulation of MPP+
  • Mice lacking α-synuclein are resistant to MPTP, showing that α-synuclein is an essential mediator of the toxic effects of complex I inhibitors
  • LRRK2 is mostly cytoplasmic, but about 10% of the protein is associated with the outer mitochondrial membrane. Overexpression of familial mutant LRRK2 protein causes caspase and Apaf-1 dependent apoptosis
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23
Q

What is MPP+?

A

Dopamine neurotoxin synthesized in the body from the precursor, MPTP.

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24
Q

What causes a change in the appearance of the substantia nigra in Parkinson’s Disease patients?

A

Loss of the pigment melanin in the substantia nigra (as well as DA neuron degeneration)

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25
Q

What are the three main processes that degrade cellular proteins? Which one is affected in Parkinson’s disease patients?

A
  • Macroautophagy
  • Microautophagy
  • Chaperone mediated autophagy (CMA)

Chaperone mediated autophagy involved in PD, by α-synuclein having a CMA recognition motif, recognized by a cytosolic chaperone.

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26
Q

How is chaperone-mediated autophagy dysfunctional in Parkinson’s disease patients. (5)

A
  • a-synuclein sequence contains a CMA recognition motif recognized by a cytosolic chaperone, the heat shock cognate protein 70 kDa (hsc70), which targets protein to the surface of lysosomes.
  • At the lysosomal membrane, the chaperone/substrate complex interacts with the lysosome-associated membrane protein type 2a (Lamp2a), which acts as a receptor in this pathway.
  • CMA activity decreases with aging.
  • Abberant α-synuclein leads to CMA dysfunction in neurons
  • mutant forms of a-synuclein strongly bound to Lamp2a and prevent subsequent translocation into the lysosome.
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27
Q

Why can schizophrenia therapy cause Parkinson’s like symptoms?

A

Because schizophrenia drugs block dopaminergic activity.

28
Q

What can dysfunction in chaperone mediated autophagy in Parkinson’s patients cause?

A

Dysfunction of chaperone-mediated autophagy can results in a-synuclein aggregation and compensative macroautophagy activation leading to cell death.

29
Q

What is Lamp2a?

A

Lysosome-associated membrane protein type 2a, acts as a receptor in the chaperone-mediated autophagy (CMA) pathway.

Aberrant α-synuclein can bind to Lamp2a to prevent translocation into the lysosome and prevent degradation of the mutated α-synuclein protein. This leads to α-synuclein aggregation and compensative macroautophagy activation, leading to cell death.

30
Q

What does PINK1 do to reduce oxidative stress? What happens with a lack of Parkin and PINK1?

A
  • PINK1 phosphorylates the intermembrane proteins TRAP-1 and HtrA2/Omi, which inhibit oxidative stress-induced Cytochrome C release and apoptosis and degrade misfolded mitochondrial protein.
  • PINK1 phosphorylates Parkin to trigger translocation of Parkin to mitochondria, where it promotes degradation of dysfunctional mitochondria in autophagosomes

Lack of Parkin and PINK1 causes mitochondrial degeneration and dopamine neuron death

31
Q

What is the DJ-1 protein?

A
  • Oxidative stress regulated chaperone and transcriptional modulator that redistributes from the cytosol to mitochondria and the nucleus upon oxidation of specific cysteine residues
  • DJ-1 also inhibits oligomerization of α-synuclein
  • DJ-1 protects against MPTP/pesticides and therefore can be important in development of pesticide-induced Parinson’s disease
32
Q

What are two dominant PD related genes, and two recessive PD related genes?

A

Dominant: LRRK1 and SNCA

Recessive: DJ-1 and Parkin

33
Q

In parkinson’s patients, there is accumulation of what metal in striatal neurons? This is associated with what protein?

A

iron

Associated with neuromelanin

34
Q

What does neuromelanin do?

A

Balances dopamine and iron concentrations

Protective function is removing catecholamines and neutralizing metal ions and binding with environmental neurotoxins

35
Q

List the Parkinson’s disease knockout mice

A
  • α-synuclein KO mice
  • LRRK2 KO mice
  • Parkin KO mice
  • PINK1 KO mice
  • DJ-1

No great mice model for typical Parkinson’s patients. Even with deletion of triple recessive PD-related genes

36
Q

What is the best way to produce mice models for Parkinson’s disease?

A

Injection of dopamine stimulants, such as amphetamines (causing lesions?)

Injection of MPTP works!

37
Q

Why is dopamine transporter imaged to diagnose Parkinson’s?

A

Reliable marker (get more info)

38
Q

What is the best drug therapy for Parkinson’s disease?

A
  • Supplying dopamine precursors (L-DOPA, Levodopa)
  • Dopamine agonists
  • Monoamine oxidase B inhibitors
  • Anticholinergics
  • Antiglutamatergics
39
Q

How does α-synuclein act like a prion?

A

By self replicating and moving from one cell to another (quite mobile)

40
Q

What is disadvantage with adenoviruses?

A

Can only carry one gene usually (small loadq

41
Q

How can gene therapy with glutamic acid decarboxylase (GAD) gene by used to treat Parkinson’s disease?

A

By converting excitatory glutamatergic neurons in the subthalamic nucleus (STN) to inhibitory GABAergic neurons.

This is to counteract the loss of nigrostriatal dopamine neurons, which cause disinhibition of STN neurons

42
Q

What can CLR01 do in Parkinson’s patients?

A

Promote α-synuclein clearance, which dose-dependently reduced apoptosis

43
Q

What processes are iron essential for?

A
  • DNA synthesis
  • Neurotransmission
  • Myelination
  • Oxygen transport, storage, activation, mitochondrial electron transport
  • Metabolism
  • Acts as coenzyme for many neurotransmitter biosynthetic enzymes (ie. DA and NE)
44
Q

Which enzyme requires iron and is a rate limiting step?

A

Tyrosine hydroxylase, rate limiting step in dopamine synthesis. May play a part in Parkinson’s, as high levels of iron were observed in dopaminergic neurons and microglia and the substantia nigra in PD patients.

45
Q

How is cellular iron controlled homeostatically? (4)

A
  • Post transcriptional regulatory action that involves two iron-regulatory proteins (IRP-1 and IRP-2), which have a role in sensing iron availability.
  • Ferrin is an iron-storage protein expressed mostly in glia whereas neuronal storage of iron involves neuromelanin.
  • Transport of iron through membranes is mediated by transferrin and its receptors (Tf and TfR1), Ferroportin (FpN), lactoferrin and its receptors (lf and LfR) and divalent metal transporter-1 (DMT1, in endosomes)
  • Iron (Fe2+) outside the neuron is oxidized to Fe3+ by ceruloplasmin (CP), endorsing its binding to Tf (transferrin)
46
Q

How is iron transported across cell membranes?

A

Transport of iron through membranes is mediated by:

  • transferrin and its receptors (Tf and TfR1),
  • Ferroportin (FpN),
  • lactoferrin and its receptors (lf and LfR)
  • divalent metal transporter-1 (DMT1, in endosomes)
47
Q

Where can the dark pigment molecule neuromelanin, be found? Why is this important?

A
  • Dopaminergic neurons of substantia nigra
  • Noradrenergic neurons of the locus coeruleus

SN and LC are the two brain areas most affected by Parkinson’s disease, which suggests that NM may be involved in the neurodegenerative process.

48
Q

How might neuromelanin be involved in iron hypothesis of Parkinson’s?

A

Neuromelanin from the substantia nigra is able to accumulate large amounts of iron, up to 33x higher than with other tissue concentrations.

49
Q

What are the three protective functions of neuromelanin?

A
  • NM synthesis removes excess catecholamines from the cytosol
  • It is able to chelate large amounts of reactive iron and other potentially toxic metals
  • It is able to bind environmental toxins, like pesticides, drugs and other toxic compounds.
50
Q

What are four toxic consequences of neuromelanin?

A
  • With high iron levels, NM accumulates iron in low affinity binding sites where it can be redox active
  • Degraded NM can release metals and toxic compounds
  • NM can induce immune based pathogenic mechanisms
  • It can induce microglia activation and release of proinflammatory factors, triggering neurodegeneration
51
Q

Name 5 mice knockouts that have investigatied genes of Parkinson’s disease

A
  • α-synuclein KO
  • LRRK2 KO
  • Parkin KO
  • PINK1 KO
  • DJ-1 KO

None are good models for Parkinson’s

52
Q

Describe α-synuclein KO mice

A

Generally unremarkable but exhibit subtle locomotor deficits, reduced striatal dopamine levels and reduction in the number of hippocampal presynaptic vesicles

53
Q

Describe LRRK2 KO mice

A

No motoric or neurochemical deficits, nor dopaminergic neurodegeneration, suggesting that LRRK2 does not play a role in the maintenance or survival of dopaminergic neurons

54
Q

Describe Parkin KO mice

A

Failed to show PD related phenotypes.

Decrease of proteins involved in mitochondrial function in the brain

55
Q

Describe PINK1 KO mice

A

Do not reveal locomotor abnormalities, protein inclusions or loss of nigrostriatal dopaminergic neurons with age.

Shows an increased number of enlarged mitochondria. Mice lacking HtrA2 reveal sever dysfunction of mitochondria, similar to that observed in PD.

56
Q

Describe DJ-1 mice

A

Fails to recreate key PD features

Cells more sensitive to dopaminergic neurotoxins

57
Q

True or false. Deletion of triple recessive PD-related genes (Parkin/PINK1/DJ-1) is not sufficient to induce striatal DA neuron degeneration.

A

True, indicating these genes are not necessary for survival.

58
Q

How can early stages of Parkinson’s be detecting with imaging?

A
  • Single photon emission computed tomography can image striatal dopaminergic neuron loss from multiplication of α-synuclein gene (SNCA)
  • PET scans show a decrease in striatal regions, when visualized for Dopamine transporter (DAT), VMAT2 and/or DDC

Imaging can also reveal progression of the disease and the direction of it (eg. lateralization etc.)

59
Q

What are two irreversible therapies for Parkinson’s and two reversible therapies?

A

Irreversible

  • Pallidotomy (destroying cells in globus pallidus to reduce dyskinesia)
  • Thalamotomy (ablating part of the thalamus to reduce tremors)
  • Cell graft therapy
  • Gene therapy with viral vectors

Reversible

  • Deep brain stimulation (thalamic, subthalamic and pallidal) to reduce tremor
  • Transcranial magnetic stimulation to treat dyskinesia
60
Q

What are three approaches to cell therapies for degenerated dopaminergic neurons?

A
  • Adrenal chromaffin cell transplatns
  • Fetal implant therapy
  • Transplantable dopamine neurons obtained from cultured pluripotent stem cells
61
Q

What are the advantages and disadvantages of cell therapy for degenerated dopamine stem cells?

A

Advantage: Cells survive, make connections, produce dopamine and integrate into neural circuits.

Disadvantages: Grafted neurons show PD pathology when disease progresses; observed dyskinesia in patients with transplants and lack of effect on the non-motor symptoms

62
Q

How is gene therapy used (or could be used) to treat Parkinson’s?

A

Adeno-associated virus (AAV) of the parvovirus family vectors is used to deliver the gene. Can’t carry long vectors.

or

Lentivirus vectors (RNA retroviruses) are used to carry multigene vectors. There is a safety concern.

63
Q

What are three therapeutic gene therapy approaches for Parkinson’s patients?

A
  • Augmentation of dopamine levels via increased NT production
  • Modulation of the neuronal phenotype by reducing the need for dopamine
  • Neuroprotection by delivery of a neurotrophin gene and in consequence, enhancing neuronal survival
64
Q

What are three enzyme replacement strategies in Parkinson’s therapy?

A

Triple delivery these into striatal neurons makes them capable of producing DA:

  • GGCH1 (GTP cyclohydrolase 1, which is RLS enzyme for tetrahydrobiopterin (BH4) cofactor for TH)
  • Tyrosine hydroxylase (TH)
  • And aromatic amino acid decarboxylase (AADC/ aka DOPA decarboxylase)

Delivery of AADC relies on peripheral administration of L-DOPA . Transduction with the TH and GCH1 genes is useful in 5-HT and DA neurons with residual AADC activity

65
Q

What type of gene therapies for Parkinson’s are under clinical trials? (4)

A
  • DOPA decarboxylase gene to putamen, patients need less L-DOPA (DA synthesis controllably carried by GABA neurons)
  • TH, GCH1 and AADC transgenes, with mutation in TH to prevent negative feedback loop (DA synthesis carried by GABA neurons, uncontrollable!)
  • Reprogramming glutamatergic cells to inhibitory GABAergic cells with delivery of GAD gene to subthalamic nucleus to increase inhibition of neurons in subthalamic nucleus (nigrostriatal neurons usually do this)
  • Neuroprotection from neurturin (NTN), member of glial derived neurotrophic factor (GDNF)
66
Q

How can the reversible and selective shut-down of pathological protein functions be achieved with drugs? How can this be used in Parkinson’s patients?

A

Molecular tweezers that can pull out cofactors from enzymes

The molecular tweezer CLR01 promotes α-synuclein clearance and reduced toxicity by inhibiting beta sheet formation and by dissolving existing fibrils (beta sheet aggregates)

67
Q

What are the two most popular inhibitor of dopamine metabolism (for treating Parkinson’s)?

A
  • COMT inhibitor

- MAO-B inhibitor

Molecular Neuroscience II (7 decks)

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