Models applicable in studying Parkinson disease: from vertebrates to invertebrates - Olasunmbo Afolayan Ph.D.
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Models applicable in studying
Parkinson disease: from
vertebrates to invertebrates
Olasunmbo Afolayan Ph.D.
Neuroscience Unit
Department of Anatomy
College of Medicine
University of Lagos
Nigeria
Outline • Overview of Parkinson disease (PD) • Pathogenesis of PD • Why modeling PD? • Criteria for selecting models for PD • Parkinson disease models • conclusion
Overview
PARKINSON DISEASE
• Is a progressive neurodegenerative movement disorder
• Affects about ~1% of population of >65 years
• Is the second most common after AD (Cabreira and Massano, 2019)
• Is the most common neurological NCD in the aging African
population (Derek et al., 2020)
• Sporadic (15% among patients) and familial (5% among patients)
Pathological hallmarks of PD
Neuropathological features
Powel et al., 2017, Nat Rev. Disease Primer
Molecular mechanism in the pathogenesis of PD
Powel et al., 2017, Nat Rev. Disease Primer
Clinical symptoms associated with Parkinson disease
Powel et al., 2017, Nat Rev. Disease Primer
Models of Parkinson Disease
Why modelling PD? • To understand the heterogeneity in the pathogenesis of PD • To design and provide test beds for novel disease- modifying therapies
Criteria for
Constructive Predictive
Animal model Face validity
validity validity
validation.Models of Parkinson Disease Chemically induced models Genetic models Combined (Chemical and Genetic) models
Chemically induced models
Cont’d
It involves the use of chemicals
such as:
• 1-methyl-4-phenyl-1,2,3,6-
tetrahydropyridine (MPTP)
• 6-hydroxydopamine (6-OHDA)
• Paraquat and Maneb
• Rotenone
A variety of vertebrates and non-
vertebrates can be used in these
models (Blesa et al., 2012).Features of chemical models
Blesa et al., 2012Genetic models
• Involves the use of genetically modified animals following the
understanding of the genetic interplay in PD.
• Genes that have been implicated with familial form of PD include:
• alpha synuclein which increases the formation of Lewy bodies
• Parkin (causes early onset of PD)
• PTEN-induced putative kinase 1 (PINK1) (shows Lewy-related pathology)
• DJ-1 (autosomal recessive PD with mild motor deficits without dopaminergic
neuron loss).
• The major disadvantage of this model is that it is unclear if the results
can be directly applied to humans.Chemical and Genetic models This involves the use of a chemical (neurotoxin) in a genetically modified animal • MPTP induces more neuronal loss in DJ-1 knockout mice Advantages: 1. captures the multifaceted nature of PD 2. might be the most ideal and most promising type of model 3. High sensitivity to neurotoxin
Animals used in modelling PD
Broadly categorized into vertebrates and invertebrates models
• Vertebrates
non-human primates- Marmosets
Rodents – Rats and mice
fishes – zebra fish
• Invertebrates
Drosophila
C. elegansVertebrates
Animals used in modelling PD Cont’d
Non-human primates
Such as the new world monkeys and old world monkeys
Advantages:
• Have anatomic, genetic, physiologic and behavioral proximity
to humans
• Functional organization of the striatal regions are similar to
humans
• Manifest many hallmarks of PD such as motor and non-motor Disadvantages:
skills
1. Ethical and
• Monkeys have better developed fine motor skills than rodents economical hurdles
• a similar hand-foot use for measuring complex motor skill such as the 2. Not suitable for
hand-eye coordination conducting pilot
• vertical body position, which allows better analysis of postural basic science
imbalances research
3. No high throughput
screeningMURINE MODEL
Advantages:
1. Biological processes between
rodents and humans are highly
conserved
2. Ability to mimic and
recapitulate some complex
pathways and features of PD
Disadvantages:
1. Ethical restrictions
2. Not suitable for high
throughput screening
3. Distinct sensitivity of
strains to neurotoxins
Photomicrograph of a 6-OHDA lesioned rat striatum immunostained for tyrosine
hydroxylase (TH). Densities of TH immunoreactivity striatal fibers are clearly reduced
after the 6- OHDA injection (right side) as compared to the densities of striatal TH-
immunoreactivity fibers in control rat (left side). Blesia et al.,2012 Journal of Biomedicine and BiotechnologyParaquat injection induced significant decrease in falling time, number of crosses and percentage alternation behaviour with a concomitant increase in the duration of cataleptic behaviour in the rotarod, open field, Y‐maze and bar tests, respectively, which was ameliorated by GPD treatment. PQT also increased lipid peroxidation, peroxynitrite and TNF‐α generations as well as deficit in superoxide dismutase and GSH activities in the midbrain. PQT‐induced oxidative stress and neuroinflammation was attenuated by GPD treatment. Findings from this study showed that GPD prevents PQT‐induced motor dysfunction, memory impairment, oxidative stress and neuroinflammation through enhancement of antioxidant defense system and inhibition of pro‐inflammatory cytokine release. Thus, GPD could be a potential adjunct in the management of Parkinsonism.
Zebrafish, Danio rerio (vertebrate)
• Are small and transparent in nature
• Neuronal circuitries involved in movement are
well characterized
• Molecular mechanism, biological and
neurobehavioural phenomenology in humans The approximate anatomical location of the dopaminergic (orange), histaminergic
(purple), noradrenergic (blue), and serotonergic (green) regions are represented in
zebrafish brain.
Vaz et al. 2018 Frontiers in Neurology
• Swimming is used in accessing dopaminergic
activity
• Reduced swimming indicates bradykinesia• Several transgenic, knockdown, and mutant zebrafish lines have been generated and characterized • Knockdown of the β- or γ1-synuclein subunits induces motor impairments • Knockout of the Parkin gene, produces a moderate (20%) loss of dopaminergic neurons, reduced mitochondrial complex I activity and increased susceptibility to toxins • However, there is no loss of dopaminergic cells when PINK1 is knocked out. however, it alters dopaminergic projections and induces locomotor deficits Saxena, 2013 material and methods. • Down regulation of PINK1 results in mitochondrial dysfunction that leads to augmented levels of ROS and activation of the apoptotic signaling pathway in zebrafish
Invertebrates
Drosophila melanogaster in PD
• Has a short life span
• About 77% of human disease genes are conserved in Drosophila
• gene sequence and function are highly conserved between flies
and humans
• Suitable for studying mechanisms of PD-related
neurodegeneration
• The brain and spinal cord are extraordinarily complex
• many PD-related genes are found to have homologues in
Drosophila
• most of DA neurons are generated at embryogenesis, matured
and gathered into clusters during first larval stage
(a) Illustration of six DA neuron clusters in Drosophila larval central brain. (b)
DA neuron clusters in Drosophila adult central brain.
Dung and Thao,2018. Advances in Experimental Medicine and BiologyDrosophila melanogaster as a model • Expression of α-synuclein in flies confers age-dependent motor difficulties and a compromise of dopaminergic neurons (Feany and Bender, 2000) • α -synuclein transgenic Drosophila models premature loss of climbing ability indicates degeneration of dopaminergic neurons and α -synuclein formation. • PINK1 Knock out in Drosophila indicates a reduction in the number of Dopaminergic neurons & impaired climbing ability.
Caenorhabditis elegans as a model
• C. elegans has an extremely rapid life cycle (4 days)
• 1/3 of its cells are made up of neurons
• 8 dopaminergic neurons are involved in motor activity
• Prolific and very amenable to genetic manipulation (Teschendorf and Link, 2009)
• The transparent nature of C. elegans throughout its life cycle facilitates the use of GFP
fusion proteins to visualize; neurons, synaptic connections and neuronal death in living
worms by the morphological appearance of vacuolated neurons (Teschendorf and Link,
2009)Caenorhabditis elegans as a model • over-expressing wild-type or mutant human α-synuclein (A53T or A30P) display degeneration of dopaminergic neurons alongside loss of the basal slowing response. • Mutations within the gene leads to the typical decrease in locomotion (basal slowing) • over-expression of wild-type LRRK2 increased survival in response to paraquat and rotenone indicating LRRK2 mutations may enhance vulnerability in PD
Conclusion An ideal model of PD should display pathophysiologic features and symptoms of PD. However, the current models are not able to recapitulate all PD features. Each model has both advantages and disadvantages, and the selection of a suitable model depends on particular purposes of the research.
Thank you for your attention.
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