ubiquilin antagonizes presenilin and promotes neurodegeneration in Drosophila

Abstract

The majority of familial Alzheimer's disease (AD) cases are caused by mutations in presenilins, therefore, identifying regulators of presenilins is crucial for understanding AD pathogenesis. Ubiquilin 1 (UBQLN1) binds Presenilins in mammalian cells; however, the functional significance of this interaction in vivo remains unclear. Moreover, while genetic variants in UBQLN1 have recently been reported to associate with an increased risk for AD, whether these variants have altered function is unknown. Here, we show that Drosophila Ubiquilin (Ubqn) binds to Drosophila Presenilin (Psn), and that loss of ubqn function suppresses phenotypes that arise from loss of psn function in vivo. In addition, overexpression of ubqn in the eye results in adult-onset, age-dependent retinal degeneration, which is at least partially apoptotic in nature. The degeneration associated with ubqn overexpression can also be suppressed by psn overexpression and enhanced by expression of a dominant negative version of Psn. Remarkably, expression of the human AD-associated variant of UBQLN1 leads to more severe degeneration than does comparable expression of the human wildtype UBQLN1. Together, these data identify Ubqn as a regulator of Psn, support an important role for UBQLN1 in AD pathogenesis, and suggest the possibility that expression of a human AD-associated variant can cause neurodegeneration independent of amyloid production.

The Parkinson's disease genes pink1 and parkin promote mitochondrial fission and/or inhibit fusion in Drosophila

“…To silence Marf, two independent regions in the Marf transcript (coding region and UTR) were independently targeted using a microRNAbased technology (38,39). To silence opa1, the coding region of opa1 transcript was targeted.…”

Ubiquilin Modifies TDP-43 Toxicity in a Drosophila Model of Amyotrophic Lateral Sclerosis (ALS)

“…In addition to our two transgenic lines, we tested a third line (UBQLN RNAi ) that knocks down the endogenous Drosophila UBQLN homolog in the tissue of interest via expression of a short hairpin RNA (22). As compared with control flies, D42-UBQLN L1 flies demonstrated slightly increased survival, D42-UBQLN L2 flies were no different, and D42-UBQLN RNAi demonstrated slightly reduced survival (supplemental Fig.…”

“…We pro-pose that changes in gene expression and/or splicing due to alterations in TDP-43 nuclear gene dosage are responsible for pathologic motor neuron death in this model of ALS. (22).…”

Functional Roles of Ubiquitin-Like Domain (ULD) and Ubiquitin-Binding Domain (UBD) Containing Proteins

“…72,73 An important role of ubiquilin proteins in AD has been further supported by in vivo studies in Drosophila, where loss of the sole ubiquilin family member, ubiquilin-1, has been linked to age-dependent neurodegeneration and reduced lifespan, processes during which it genetically interacts with the presenilins. 74,75 Interestingly, ubiquilins have been found to interact with Eps15, a binding event that by extension suggests a putative model in which ubiquilin-1/2 plays crucial roles during the trafficking of protein aggregates to the aggresome. 68,76 Figure 4.…”