Interplay Between the Autophagy-Lysosomal Pathway and the Ubiquitin-Proteasome System: A Target for Therapeutic Development in Alzheimer's Disease

Abstract

Alzheimer's disease (AD) is the most common cause of age-related dementia leading to severe irreversible cognitive decline and massive neurodegeneration. While therapeutic approaches for managing symptoms are available, AD currently has no cure. AD associates with a progressive decline of the two major catabolic pathways of eukaryotic cells-the autophagy-lysosomal pathway (ALP) and the ubiquitin-proteasome system (UPS)-that contributes to the accumulation of harmful molecules implicated in synaptic plasticity and long-term memory impairment. One protein recently highlighted as the earliest initiator of these disturbances is the amyloid precursor protein (APP) intracellular C-terminal membrane fragment β (CTFβ), a key toxic agent with deleterious effects on neuronal function that has become an important pathogenic factor for AD and a potential biomarker for AD patients. This review focuses on the involvement of regulatory molecules and specific post-translational modifications (PTMs) that operate in the UPS and ALP to control a single proteostasis network to achieve protein balance. We discuss how these aspects can contribute to the development of novel strategies to strengthen the balance of key pathogenic proteins associated with AD.

Keywords: Alzheimer’s disease; HSV-1; autophagy; lysosomes; neuronal dysfunction; proteasome; proteostasis; ubiquitin.

Figure 1

Autophagy-lysosomal pathway (ALP) and ubiquitin-proteasome system (UPS) pathways under normal and pathological conditions. Proteins are tagged with ubiquitin conjugates through a sequential enzymatic mechanism involving three classes of enzymes, E1, E2 and E3. Under normal conditions, ubiquitylated substrates are recognized by ubiquitin receptors present in ALP and UPS pathways and efficiently eliminated. In the UPS, substrates are subsequently deubiquitylated by RPN11, a key step for substrate degradation and amino acid recycling. Free-Ub chains formed by RPN11 activity promote ALP function. Ubiquitin receptors in the ALP, in contrast to the UPS, form oligomers to facilitate substrate recognition and autophagosomal recruitment. Under aging and Alzheimer’s disease conditions there is a decrease in the function of the ALP and the UPS that reduces substrate degradation and amino acid recycling. Downregulation of RPN11 in Alzheimer’s disease (AD) decreases free-Ub chains disrupting substrate recognition, their recruitment into autophagosomes and their final degradation by the ALP. Altogether, leading to the accumulation of deleterious protein aggregates. Transcriptional regulation (Nrf1/2) and phosphorylation (kinases/phosphatases) play a crucial role in ALP and UPS function whereas their dysregulation is the focus of intense studies in aging and Alzheimer’s disease.