α-Synuclein Transgenic Drosophila As a Model of Parkinson's Disease and Related Synucleinopathies

Table 2

Summary of studies on α-Syn-induced neurodegeneration using Drosophila models.

Mechanisms/modifiers of α-Syn toxicity	Effect	Findings	References
α-Syn expression		α-Syn expression causes dopaminergic neuron loss, LB-like inclusion body formation and locomotor dysfunction in Drosophila (wild-type < familial PD-linked mutants).	[12]
Misfolding and aggregation
α-Syn oligomer formation	Enhance	α-Syn mutants which tend to form oligomers enhance α-Syn toxicity.	[18]
HDAC6	Suppress	Expression of HDAC6 reduces α-Syn oligomers and suppresses α-Syn toxicity.	[19]
HSP70	Suppress	Expression of HSP70 reduces α-Syn toxicity, and a dominate negative form of HSP70 enhances toxicity.	[20]
Geldanamycin	Suppress	Geldanamycin induces HSP70 expression and suppresses α-Syn toxicity.	[21]
Ubiquitin	Suppress	Expression of ubiquitin reduces α-Syn toxicity.	[22]
Cathepsin D	Suppress	Deficiency of cathepsin D enhances α-Syn-induced neurodegeneration.	[23]
Posttranslational modifications
α-Syn phosphorylation at Ser129	Enhance	A phosphomimic S129D α-Syn mutant enhances α-Syn toxicity and a phospho-resistant S129A α-Syn mutant reduces toxicity.	[24]
α-Syn phosphorylation at Tyr125	Suppress	Expression of shark increases α-Syn Y125 phosphorylation and reduces α-Syn toxicity. Blocking of Y125 phosphorylation enhances toxicity.	[25]
α-Syn C-terminal truncation	Enhance	Expression of C-terminal truncated α-Syn (1–120) enhances α-Syn aggregation and toxicity.	[26]
α-Syn cleavage by Calpain I	Enhance	Calpain I-cleaved α-Syn fragments were identified in the brains of α-Syn flies as well as PD/DLB patients.	[27]
Oxidative stress
Reactive oxygen species	Enhance	Hypoxia-induced oxidative stress enhances α-Syn toxicity, and expression of superoxide dismutase suppresses toxicity.	[28]
Dopamine	Enhance	Decreased dopamine levels by tyrosine hydroxylase RNAi reduces α-Syn toxicity.	[29]
Glutathione metabolism	Suppress	Defect of glutathione metabolism genes enhances α-Syn toxicity and expression of glutathione metabolism genes suppresses toxicity.	[30]
Nicotinamide	Suppress	Nicotinamide suppresses α-Syn toxicity through improvement of oxidative mitochondrial dysfunction.	[31]
Polyphenols	Suppress	Grape extracts containing various polyphenols suppress α-Syn toxicity.	[32]
Other PD-causing genes
Parkin	Suppress	Expression of Parkin suppresses α-Syn toxicity.	[33–35]
PINK1	Suppress	Expression of PINK1 suppresses α-Syn toxicity.	[36]