• cognitive disorder

This report describes a Drosophila model of cognitive/behavioral disorders for which the human PRODH gene is implicated (see MIM:606810). PRODH is implicated in hyperprolinemia type I (MIM:239500), which in its most severe forms is associated neurologic phenotypes, including epilepsy and intellectual disability; PRODH has also been postulated to be a susceptibility locus for schizophrenia (MIM:600850). PRODH encodes proline dehydrogenase 1, a protein localized on the inner mitochondrial membrane that catalyzes the first step in the degradation of the amino acid proline. There is a single orthologous gene in Drosophila, slgA, for which a loss-of-function mutation, RNAi-targeting constructs, and alleles caused by insertional mutagenesis have been generated. Although more closely related to PRODH, Dmel\slgA is also orthologous to the human gene PRODH2.

A UAS construct carrying the wild-type human Hsap\PRODH gene as been introduced into flies. Overexpression of the human gene in specific sets of neurons (LNv neurons) in the adult brain results in a significant increase in aggressive behavior; LNv neurons are known to be involved in the generation of adult locomotor rhythms.

Animals hemizygous for a loss-of-function mutation of Dmel\slgA exhibit reduced viability, defective phototaxis, and uncoordinated behavior. RNAi-effected knockdown of the Dmel\slgA gene in LNv neurons results in an increase in aggressive behavior; overexpression of distinct isoforms of slgA also leads to hyperaggressive behavior. Since hyperaggression is observed for both overexpression (of the human gene or the fly gene) and decreased expression (of the fly gene), it appears that proline metabolism must be tightly controlled to maintain normal behavior. A single physical interaction has been described for Dmel\slgA; see below and in the slgA gene report.

[updated Feb. 2019 by FlyBase; FBrf0222196]