The ubiquitin-proteasome system in neurodegenerative diseases: precipitating factor, yet part of the solution

Abstract

The ubiquitin-proteasome system (UPS) has been implicated in neurodegenerative diseases based on the presence of deposits consisting of ubiquitylated proteins in affected neurons. It has been postulated that aggregation-prone proteins associated with these disorders, such as α-synuclein, β-amyloid peptide, and polyglutamine proteins, compromise UPS function, and delay the degradation of other proteasome substrates. Many of these substrates play important regulatory roles in signaling, cell cycle progression, or apoptosis, and their inadvertent stabilization due to an overloaded and improperly functioning UPS may thus be responsible for cellular demise in neurodegeneration. Over the past decade, numerous studies have addressed the UPS dysfunction hypothesis using various model systems and techniques that differ in their readout and sensitivity. While an inhibitory effect of some disease proteins on the UPS has been demonstrated, increasing evidence attests that the UPS remains operative in many disease models, which opens new possibilities for treatment. In this review, we will discuss the paradigm shift that repositioned the UPS from being a prime suspect in the pathophysiology of neurodegeneration to an attractive therapeutic target that can be harnessed to accelerate the clearance of disease-linked proteins.

Polyubiquitinylation Profile in Down Syndrome Brain Before and After the Development of Alzheimer Neuropathology

“…Recent studies from our group and others demonstrated that disturbance of proteolytic machinery is a key feature of degenerating neurons and appears in several neurodegenerative disorders (4,8,15). Proteasome activity was found to be reduced in AD brains than in age-matched controls (38,50) and also in DS brain (17).…”

Regulation of Mitochondrial Dynamics by Proteolytic Processing and Protein Turnover

“…Similar phenomena occur in mammalian models of disease when proteasomal function is inhibited or dysfunctional due to genetic alterations. Neurodegenerative diseases often display proteasomal defects due to accumulation of neurotoxic molecules such as alpha-synuclein, beta-amyloid or mutant huntingtin that can act as inhibitors of proteasome activity or by overwhelming proteasome activity [32]. Proteasomal involvement in regulation of mitochondrial function is also demonstrated by a number of proteasome components and ubiquitin E3 ligases that associate on the surface of the OMM, such IBRDC2, FBXW7, FBXO7, RFN185 in humans and Rsp5 and Dma1 in budding yeast (see references in [33].…”

Cerebrospinal Fluid Biomarkers for Huntington’s Disease

“…Ubiquitin is added post-transcriptionally to flag proteins for degradation by the ubitiquitin-proteaseome system (UPS), and its elevation in CSF may reflect the gradual accumulation of unwanted proteins, perhaps including mHTT, in cells of the CNS. Failure of the UPS to cope with the buildup of abnormal proteins is suggested to be involved in the pathogenesis of HD and other neurodegenerative diseases [82]. This finding warrants further investigation and its longitudinal predictive value needs to be determined in a suitable patient cohort.…”