Targeting ubiquilin-1 in Alzheimer's disease

Abstract

Introduction: Alzheimer's disease (AD) is a common neurodegenerative disorder affecting an increasing number of people worldwide as the population ages. Currently, there are no drugs available that could prevent AD pathogenesis or slow down its progression. Increasing evidence links ubiquilin-1, an ubiquitin-like protein, into the pathogenic mechanisms of AD and other neurodegenerative diseases. Ubiquilin-1 has been shown to play a key role in the regulation of the levels, subcellular targeting, aggregation and degradation of various neurodegenerative disease-associated proteins. These include the amyloid precursor protein and presenilins that are intimately involved in the mechanisms of AD.

Areas covered: Here, the properties and diverse functions of ubiquilin-1 protein in the context of the pathogenesis of AD and other neurodegenerative disorders are discussed. This review recapitulates the available knowledge on the involvement of ubiquilin-1 in the genetic and molecular mechanisms in AD. Furthermore, the association of ubiquilin-1 with specific proteins and mechanisms involved in the pathogenesis of neurodegenerative diseases is described and the known ubiquilin-1-interacting proteins summarized.

Expert opinion: The variety of ubiquilin-1-interacting proteins and its central role in the regulation of protein levels and degradation provides a number of novel candidates and approaches for future research and drug discovery.

Keywords::

• aggresome
• Alzheimer's disease
• amyloid precursor protein
• autophagy
• β-amyloid, endoplasmic reticulum stress
• presenilin
• proteasome
• secretase
• ubiquitin-associated domain
• ubiquitin-like domain

Acknowledgment

M Takalo and A Haapasalo contributed equally to this paper.

Declaration of interest

This study was supported by the Health Research Council of the Academy of Finland, EVO grant 5772708 of Kuopio University Hospital, the Strategic Funding of the University on Eastern Finland (UEF-Brain) and Sigrid Juselius Foundation. The authors state no conflict of interest and have received no payment in preparation of this manuscript.

Notes

This box summarizes key points contained in the article.