Roles of α-Synuclein and Disease-Associated Factors in Drosophila Models of Parkinson’s Disease
Abstract
:1. Introduction
2. Modelling PD by αSyn Expression in Drosophila
3. Familial PD-Causing Mutations of αSyn
4. Genetic Interactions of αSyn with Familial PD-causing Genes
5. Genetic Interaction of αSyn with Risk Genes for Sporadic PD
6. Nongenetic Factors of PD
7. Concluding Remarks
Funding
Institutional Review Board Statement
Acknowledgments
Conflicts of Interest
Abbreviations
αSyn | α-synuclein |
PD | Parkinson’s disease |
DA | Dopaminergic |
LBs | Lewy bodies |
GWAS | Genome-wide association study |
SNPs | Single nucleotide polymorphisms |
WT | Wild-type |
RNAi | RNA interference |
UAS | upstream activating sequence |
Fly-VRL | Fly vertically rotating arena for locomotion |
FlyConTra | Fly Contour-based Tracker |
TH | Tyrosine hydroxylase |
LM | Light microscopy |
ERG | Electroretinography |
PK | Proteinase K |
QUAS | QF upstream activating sequence |
ddc | 3,4-dihydroxyphenylalanine-1-decarboxylase |
elav | embryonic lethal abnormal vision |
GMR | glass multiple reporter |
PINK1 | PTEN-induced putative kinase 1 |
PLA2G6 | Phospholipase A2 G6 |
LRRK2 | Leucine rich-repeat kinase 2 |
VPS35 | Vacuolar protein sorting 35 |
DNAJC13 | DnaJ heat shock protein family member C13 |
CHCHD2 | Coiled-coil-helix-coiled-coil-helix domain-containing protein 2 |
DLB | Dementia with Lewy bodies |
HtrA2 | High temperature requirement protein A2 |
GBA1 | β-glucocerebrosidase 1 |
GCase | Glucocerebrosidase |
GD | Gaucher’s disease |
GlcCer | Glucosylceramide |
ARSA | Arylsulfatase A |
MAPT | Microtubule-associated protein Tau |
BST1 | Bone marrow stromal cell antigen 1 |
Ric | Ras-related protein interacting with calmodulin |
Vps13 | Vacuolar protein sorting 13 |
GAK | Cyclin-G-associated kinase |
RIT2 | Ras like without CAAX 2 |
Nrf2 | Nuclear factor erythroid 2-related factor 2 |
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Advantage | Note |
---|---|
(1) Analysis of gene functions in vivo | Encode homologues of more than 75% of human disease genes |
(2) Rapid generation cycle and short lifespan | 10–14 days from embryo to adult |
Lifespan of 60–80 days | |
(3) Well-maintained information | Flybase 1, the leading database for genomic and genetic information of Drosophila, is linked to a wide range of other available tools |
(4) Abundant useful tools for genetic analysis | Genome-wide mutant and RNAi fly libraries |
Cell-type- and temporal-specific gene expression systems | |
Genome editing systems | |
(5) Little labor and cost-effective | Transgenic flies can be established relatively easily at low cost |
Mutant, RNAi, and transgenic flies are available from public stock centers at low cost | |
Small space is required for their maintenance |
Category of Phenotype | Specific Phenotype Evaluated | Assay |
---|---|---|
Behavior | Locomotor dysfunction | Climbing assay, automated tracking systems |
Abnormal sleep behavior, circadian rhythm | Drosophila Activity Monitor system | |
Olfactory deficits | Odor acuity/discrimination assay | |
Anxiety | Open-field assay | |
Cognitive dysfunction | T-maze assay | |
Lifespan | Lifespan assay | |
Neurodegeneration | DA neuron loss | Counting DA neurons either by tyrosine hydroxylase staining or reporter expression |
Compound eye degeneration | Observation of external eye appearance by light microscopy, scanning electron microscopy, or analysis of retina tissue sections | |
Neuronal dysfunction | Electrical activity of the retina | Electroretinography |
Electrical activity of brain or motor neurons | Electrophysiological recordings from projection neurons or neuromuscular junction | |
αSyn accumulation/inclusion formation | αSyn inclusions | Immunohistochemistry with an αSyn antibody |
αSyn aggregation | Immunoblotting of lysates separated by detergent | |
Pathological αSyn conformers | Immunohistochemistry with an αSyn antibody after proteinase K (PK) treatment | |
Immunoblotting of lysates treated with PK | ||
αSyn oligomers | Biomolecular fluorescence complementation assay |
Reference (Corresponding Author) | Modifications | Driver Line 1 | Behavior /Neuronal Function | Histology /Biochemistry | Notes |
---|---|---|---|---|---|
L.J. Pallanck [40] | Added Kozak sequence (CAAA) and used strains bearing 2 copies of transgenes | TH-GAL4 | DA neurons at PPL1 ↓ (20 days) | 2–5-fold higher αSyn protein level than previously reported lines (Feany [18], Bonini [43]) | |
J.M. Shulman [32] | Codon optimization for Drosophila | Rh1-GAL4 | Progressive ERG abnormalities (1–30 days) | Retina and photoreceptor degeneration (10–30 days) | 20-fold increase in αSyn protein level than non-codon optimized line |
M.B. Feany [42] | Q system | Syb-QF2 | Locomotor dysfunction (>7 days) | Brain vacuolization, cortical neuron ↓ (>10 days) Inclusion + (>1 days) | Using the Q-system yielded higher levels of αSyn than using the GAL4/UAS system |
Reference (Corresponding Author) | SNCA Variant | Driver Line 1 | Behavior /Neuronal Function | Histology /Biochemistry | Notes |
---|---|---|---|---|---|
M.B. Feany [18] | WT A30P A53T | ddc-GAL4 | DA neuron ↓ (30–60 days) Inclusions (1 day) | ||
elav-GAL4 | Locomotor dysfunction (A30P > A53T, WT, >23 days) | DA neuron ↓ (30–60 days) Inclusions (20–30 days) αSyn neuritic pathology (60 days) | |||
GMR-GAL4 | Retinal degeneration (10–30 days) | ||||
N.M. Bonini [43] | WT A30P A53T | ddc-GAL4 | DA neuron ↓ (A30P > A53T > WT, 20 days) Inclusions + (ubiquitin +) αSyn neuritic pathology (20 days) | ||
T. Iwatsubo [44] | WT A30P A53T | elav-GAL4 | Phosphorylation of αSyn at S129 (A53T > A30P > WT) | ||
G. Mardon [45] | WT A30P A53T | ddc-GAL4 | No changes in DA neuron number (30 days) | No changes in DA neuron number were found in the Feany [18] and Bonini [43] lines | |
elav-GAL4 | No changes in locomotor function (up to 38 days) | ||||
GMR-GAL4 | No changes in ommatidial morphology (40 days) | ||||
S.K. Maji [46] | WT E46K H50Q G51D | elav-GAL4 | Locomotor dysfunction (G51D > E46K > WT, H50Q, >30 days) Shortened lifespan (G51D, H50Q, E46K > WT) | DA neuron ↓ (30 days) αSyn oligomers (H50Q, G51D, E46K > WT, >10 days) | |
Y. Nagai [47] | WT A30P E46K H50Q G51D A53T | GMR-GAL4 | Mild eye degeneration (1 day) E46K αSyn accumulation (1 day) | Site-specific transgenesis to express equivalent transcriptional levels of αSyn | |
nSyb-GAL4 | Locomotor dysfunction (E46K, H50Q, H50Q, and A53T at 3 weeks, all lines at 5 weeks) | E46K αSyn protein accumulation (1 day) | |||
M. Haddadi [48] | WT E46K | GMR-GAL4 | Irregular organization of ommatidia, loss of bristles (10 days) Retinal neuron degeneration | ||
ddc-GAL4 | Locomotor dysfunction (>20 days) Paraquat sensitivity↑ | DA neuron ↓ (E46K > WT) | |||
elav-GAL4 | Short lifespan (E46K) Ethanol sensitivity↑ |
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Suzuki, M.; Sango, K.; Nagai, Y. Roles of α-Synuclein and Disease-Associated Factors in Drosophila Models of Parkinson’s Disease. Int. J. Mol. Sci. 2022, 23, 1519. https://doi.org/10.3390/ijms23031519
Suzuki M, Sango K, Nagai Y. Roles of α-Synuclein and Disease-Associated Factors in Drosophila Models of Parkinson’s Disease. International Journal of Molecular Sciences. 2022; 23(3):1519. https://doi.org/10.3390/ijms23031519
Chicago/Turabian StyleSuzuki, Mari, Kazunori Sango, and Yoshitaka Nagai. 2022. "Roles of α-Synuclein and Disease-Associated Factors in Drosophila Models of Parkinson’s Disease" International Journal of Molecular Sciences 23, no. 3: 1519. https://doi.org/10.3390/ijms23031519