Dysregulation of Ubiquitin-Proteasome System in Neurodegenerative Diseases

Abstract

The ubiquitin-proteasome system (UPS) is one of the major protein degradation pathways, where abnormal UPS function has been observed in cancer and neurological diseases. Many neurodegenerative diseases share a common pathological feature, namely intracellular ubiquitin-positive inclusions formed by aggregate-prone neurotoxic proteins. This suggests that dysfunction of the UPS in neurodegenerative diseases contributes to the accumulation of neurotoxic proteins and to instigate neurodegeneration. Here, we review recent findings describing various aspects of UPS dysregulation in neurodegenerative disorders such as Alzheimer's disease, Parkinson's disease, and Huntington's disease.

Keywords: Alzheimer’s disease; Huntington’s disease; Parkinson’s disease; deubiquitinating enzyme; proteasome; ubiquitin.

FIGURE 1

Ubiquitination and ubiquitin-proteasome system. Ubiquitination is a posttranslational modification that the ubiquitin is covalently conjugated to a Lysine residue of the substrate proteins. Ubiquitin is first attached to a Cysteine residue (the active-site) of ubiquitin activating enzyme (E1 ligase) in an ATP-dependent reaction. Subsequently, the activated ubiquitin will be transferred to a Cysteine residue of conjugating enzyme (E2 ligase). Finally, working with a specific E3 ligase, E2 ligase can transfer the (poly)ubiquitin to a Lysine residue of the substrate. There are three major classes of E3 ligases, including RING E3 ligases, HECT E3 ligases, and RBR E3 ligases. RING E3 ligases catalyze the transfer of ubiquitin directly from E2 ligases to the substrate. However, the activated ubiquitin is first transferred from E2 ligases to HECT or RBR E3 ligases and then be transferred to the substrate from the E3 ligases. Lys48-linked polyubiquitin chains usually target proteins for proteasomal degradation, whereas Lys63-linked polyubiquitination is involved in regulation of NFκB signaling. Lys27-linked polyubiquitination is important in regulating mitophagy, and Lys11-linked polyubiquitin chains are implicated in cell cycle regulation. Ubiquitination is reversed by deubiquitinating enzymes (DUBs). DUBs are crucial for determining the fate of ubiquitinated proteins through removing/editing the length/type of polyubiquitin chains. In addition, DUBs can disassemble unanchored ubiquitin chains for ubiquitin recycling.