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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.

ubiquilin antagonizes presenilin and promotes neurodegeneration in Drosophila