Therapeutic Intervention at Cellular Quality Control Systems in Alzheimers and Parkinsons Diseases

Daniela      M. Arduino; A.      Raquel Esteves; Diana      F.F. Silva; Diogo      Martins-Branco; Daniel      Santos; Diana      F. Gomes Pimentel; Sandra      M. Cardoso

doi:10.2174/138161211798072481

Abstract

Cellular homeostasis relies on quality control systems so that damaged biologic structures are either repaired or degraded and entirely replaced by newly formed proteins or even organelles. The clearance of dysfunctional cellular structures in long-lived postmitotic cells, like neurons, is essential to eliminate, per example, defective mitochondria, lipofuscin-loaded lysosomes and oxidized proteins. Short-lived proteins are degraded mainly by proteases and proteasomes whether most long-lived proteins and all organelles are digested by autophagy in the lysosomes. Recently, it an interplay was established between the ubiquitin-proteasome system and macroautophagy, so that both degradative mechanisms compensate for each other. In this article we describe each of these clearance systems and their contribution to neuronal quality control. We will highlight some of the findings that provide evidence for the dysfunction of these systems in Alzheimers and Parkinsons diseases. Ultimately, we provide an outline on potential therapeutic interventions based on the modulation of cellular degradative systems.

Keywords: Macroautophagy, proteasome, ubiquitin, protein aggregates, mitochondria, Parkin-mediated mitophagy, neurodegeneration, oxidative stress, Aβ peptide, apoptosis