• Parkinson's disease

This report describes a Parkinson-like neurodegenerative disease model using the Drosophila Pgk gene. Dmel\Pgk is orthologous to two human genes, PGK1 and PGK2, which encode phosphoglycerate kinases that catalyze an ATP-producing step in the glycolytic pathway. Loss-of-function mutations, RNAi targeting constructs, and alleles caused by insertional mutagenesis have been generated for Dmel\Pgk.

PGK1 is located within a region defined as a susceptibility locus for familial Parkinson disease, PARK12 (see MIM:300557); this gene is also associated with the recessive X-linked disease, Phosphoglycerate kinase 1 deficiency (MIM:300653). A UAS construct of a tagged wild-type copy of Hsap\PGK1 has been introduced into flies, but has not been characterized. Expression of PGK2 is testis-specific and thus it is not considered a candidate causative gene for Parkinson disease.

Homozygous loss-of-function mutations of Dmel\Pgk are lethal; animals typically die in the pupal stage. In this model, pan-neuronal or dopaminergic (DA) neuron-specific knockdown of Pgk via RNAi has been assessed. Reduction of Pgk in DA neurons results in locomotor defects in both young and aged adult flies and progressive DA neuron loss with aging; decreased dopamine levels are observed in the central nervous system (CNS) of young and aged adult flies. Pan-neuronal reduction induces low ATP levels and the accumulation of reactive oxygen species (ROS) in the CNS of third instar larvae.

[updated Oct. 2020 by FlyBase; FBrf0222196]