Genetic modulation of polyglutamine toxicity by protein conjugation pathways in Drosophila

Abstract

Spinal and bulbar muscular atrophy (SBMA) is a heritable neurodegenerative disease caused by the expansion of a polyglutamine [poly(Q)] repeat within the androgen receptor (AR) protein. We studied SBMA in Drosophila using an N-terminal fragment of the human AR protein. Expression of a pathogenic AR protein with an expanded poly(Q) repeat in Drosophila results in nuclear and cytoplasmic inclusion formation, and cellular degeneration, preferentially in neuronal tissues. We have studied the influence of ubiquitin-dependent modification and the proteasome pathway on neural degeneration and AR protein fragment solubility. Compromising the ubiquitin/proteasome pathway enhances degeneration and decreases poly(Q) protein solubility. Our data further suggest that Hsp70 and the proteasome act in an additive manner to modulate neurodegeneration. Through the over-expression of a mutant of the SUMO-1 activating enzyme Uba2, we further show that poly(Q)-induced degeneration is intensified when the cellular SUMO-1 protein conjugation pathway is altered. These data suggest that post-translational protein modification, including the ubiquitin/proteasome and the SUMO-1 pathways, modulate poly(Q) pathogenesis.

Heat Shock Protein 70 Participates in the Neuroprotective Response to Intracellularly Expressed β-Amyloid in Neurons

“…In support of this hypothesis, Hsp70 family members have been shown to interact with intracellular A␤ when expressed in the cytosolic compartment of a transgenic Caenorhabditis elegans model (Fonte et al, 2002). Because Hsp70 has roles in preventing protein aggregation and promoting protein degradation (Muchowski et al, 2000;Dul et al, 2001;Chan et al, 2002;Dou et al, 2003), it is plausible that Hsp70 is critical in the sequestration of intraneuronal A␤. Alternatively, Hsp70 may prevent A␤ from interacting with cell survival proteins (Suhara et al, 2003).…”

DeSUMOylating enzymes—SENPs

“…There is building evidence that SUMO is involved in the pathology of neurodegenerative disorders, including Huntington's, Parkinson's, and Alzheimer's diseases. SUMOylation of huntingtin increases its neurotoxicity both in cultured human neurons and in a Drosophila model of Huntington's disease (54,55). Another study (56) showed that neuronal intranuclear inclusions caused by overexpressing of truncated atrophin-1 with expanded polyglutamine stretches colocalized with SUMO-1 in the ataxia dentatorubral-pallidoluysian atrophy, whereas cotransfection of mutant SUMO-1 that cannot be covalently attached decreased number of aggregates.…”

Nouvelles fonctions extranucléaires de la sumoylation des protéines dans le système nerveux central

“…De plus, la réduction de l'expression de SUMO-1 diminue la dégénérescence neuronale dans ce modèle génétique de maladie de Huntington [27]. Inversement, l'inhibition de la voie de sumoylation augmente de manière significative la neurodégénérescence dans un modèle de SBMA [28]. Il est par conséquent important de constater qu'un équi-libre entre ubiquitinylation et sumoylation est essentiel pour le contrôle à la fois de la stabilité et l'adressage cellulaire de ces protéines et que cette balance est dérégulée dans ces deux maladies.…”