Déjà vu with a twist: transglutaminases in bioenergetics and transcriptional dysfunction in Huntington's disease.

The article by McConoughey et al in the current issue of EMBO Molecular Medicine examines the contribution of transglutaminase 2 (TG2) to Huntington's disease (HD) pathogenesis. The authors find that TG2 inhibition can ameliorate HD neurodegeneration, and thereby elevate the status of transglutaminases (TGs) to a major therapeutic target-not because of their well-known activity in mutant protein aggregation, but instead based upon their ability to epigenetically modulate transcription and energy production. While the reintroduction of TG inhibition as a therapy for HD may evoke feelings of déjà vu, the outcome this time around could go in a dramatically different direction.

Proteomics of dense core secretory vesicles reveal distinct protein categories for secretion of neuroeffectors for cell-cell communication.

Regulated secretion of neurotransmitters and neurohumoral factors from dense core secretory vesicles provides essential neuroeffectors for cell-cell communication in the nervous and endocrine systems. This study provides comprehensive proteomic characterization of the categories of proteins in chromaffin dense core secretory vesicles that participate in cell-cell communication from the adrenal medulla. Proteomic studies were conducted by nano-HPLC Chip MS/MS tandem mass spectrometry.

A Drosophila ortholog of the human MRJ modulates polyglutamine toxicity and aggregation.

In the Drosophila eye, proteins with an expanded polyglutamine (polyQ) tract form nuclear and cytoplasmic inclusions and produce cytotoxicity, demonstrated as loss of eye pigmentation and structural integrity. An EP P-element that suppressed the loss of eye pigmentation was inserted 9.7 kb upstream of dmrj, a gene that encodes an ortholog of a brain-enriched cochaperone, the human MRJ (mammalian relative of DnaJ).

Evidence for sequestration of polyglutamine inclusions by Drosophila myeloid leukemia factor.

Intracellular inclusions of abnormally long polyglutamine tracts and neurotoxicity are the hallmarks of several hereditary neurodegenerative disorders, including Huntington's disease (HD). In Drosophila melanogaster, dMLF, an ortholog of human myeloid leukemia factors, hMLF1 and hMLF2, suppressed polyglutamine toxicity and colocalized with the inclusions. In transfected primary rat neuronal cultures, dMLF and its orthologs reduced the morphological phenotypes and inclusions.

Multiple-stress analysis for isolation of Drosophila longevity genes.

Long-lived organisms tend to be more resistant to various forms of environmental stress. An example is the Drosophila longevity mutant, methuselah, which has enhanced resistance to heat, oxidants, and starvation. To identify genes regulated by these three stresses, we made a cDNA library for each by subtraction of "unstressed" from "stressed" cDNA and used DNA hybridization to identify genes that are regulated by all three.

Aberrant histone acetylation, altered transcription, and retinal degeneration in a Drosophila model of polyglutamine disease are rescued by CREB-binding protein.

Sequestration of the transcriptional coactivator CREB-binding protein (CBP), a histone acetyltransferase, has been implicated in the pathogenesis of polyglutamine expansion neurodegenerative disease. We used a Drosophila model to demonstrate that polyglutamine-induced neurodegeneration is accompanied by a defect in histone acetylation and a substantial alteration in the transcription profile. Furthermore, we demonstrate complete functional and morphological rescue by up-regulation of endogenous Drosophila CBP (dCBP).

Suppression of polyglutamine toxicity by a Drosophila homolog of myeloid leukemia factor 1.

The toxicity of an abnormally long polyglutamine [poly(Q)] tract within specific proteins is the molecular lesion shared by Huntington's disease (HD) and several other hereditary neurodegenerative disorders. By a genetic screen in Drosophila, devised to uncover genes that suppress poly(Q) toxicity, we discovered a Drosophila homolog of human myeloid leukemia factor 1 (MLF1). Expression of the Drosophila homolog (dMLF) ameliorates the toxicity of poly(Q) expressed in the eye and central nervous system.