Dysfunctional Ubiquitination: A Critical Signaling Process in Neurodegenerative Diseases and a Protac Target

Introduction

Neurodegenerative diseases are characterized by the progressive deterioration of the nervous system, a phenomenon marked by the selective loss of vulnerable neuronal populations. Aging is the most prominent risk factor for numerous neurodegenerative disorders, including Alzheimer's and Parkinson's diseases (AD and PD, respectively)1.  A hallmark feature of neurodegeneration is the accumulation of misfolded proteins within the brain. These protein aggregates can arise from disease-associated gene mutations or disruptions in protein homeostasis2. Cells employ two major protein degradation pathways, the ubiquitin-proteasome system (UPS)3 and the autophagy-lysosome pathway (ALP)4 to eliminate unnecessary or misfolded proteins and maintain cellular integrity. Both pathways involve ubiquitination, a process that utilizes ubiquitin (Ub) to tag proteins for degradation. Beyond its role in protein degradation, ubiquitin signaling plays a critical role in maintaining cellular homeostasis, a process essential for neuronal function and survival. With advancing age, there is a decline in the efficiency of both UPS and ALP, leading to the accumulation of potentially neurotoxic protein aggregates such as Amyloid β (Aβ), tau, α-synuclein, SOD1, and TDP-43, where Ub is frequently observed5. This Newsletter will discuss current knowledge about ubiquitination in neurodegenerative diseases, including underlying mechanisms and potential therapeutic targets.

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