The Ubiquitin-Proteasome System and Molecular Chaperone Deregulation in Alzheimer’s Disease

Abstract

One of the shared hallmarks of neurodegenerative diseases is the accumulation of misfolded proteins. Therefore, it is suspected that normal proteostasis is crucial for neuronal survival in the brain and that the malfunction of this mechanism may be the underlying cause of neurodegenerative diseases. The accumulation of amyloid plaques (APs) composed of amyloid-beta peptide (Aβ) aggregates and neurofibrillary tangles (NFTs) composed of misfolded Tau proteins are the defining pathological markers of Alzheimer's disease (AD). The accumulation of these proteins indicates a faulty protein quality control in the AD brain. An impaired ubiquitin-proteasome system (UPS) could lead to negative consequences for protein regulation, including loss of function. Another pivotal mechanism for the prevention of misfolded protein accumulation is the utilization of molecular chaperones. Molecular chaperones, such as heat shock proteins (HSPs) and FK506-binding proteins (FKBPs), are highly involved in protein regulation to ensure proper folding and normal function. In this review, we elaborate on the molecular basis of AD pathophysiology using recent data, with a particular focus on the role of the UPS and molecular chaperones as the defensive mechanism against misfolded proteins that have prion-like properties. In addition, we propose a rational therapy approach based on this mechanism.

Rbfox Splicing Factors Maintain Skeletal Muscle Mass by Regulating Calpain3 and Proteostasis

“…It is interesting that increased levels of Calpn3 lacking exons 15 and 16 are as detrimental to myofibers as loss-of-function mutations in Capn3, which are the most common cause of limb girdle muscular dystrophy type 2A (LGMD2A), a childhood-onset, progressive disease. The dramatic skeletal muscle phenotype in the Rbfox-DKO mouse provides clear evidence not only of the importance of alternative splicing for the maintenance of adult muscle mass but also of the sensitivity of muscle to alterations in proteostasis, as has been observed for the brain (Navone et al, 2015; Smith et al, 2015; Sulistio and Heese, 2016). …”

Life and death in the trash heap: The ubiquitin proteasome pathway and UCHL1 in brain aging, neurodegenerative disease and cerebral Ischemia

“…These toxins include abnormally folded or aggregated proteins (Haass and Selkoe, 2007). Neurodegenerative diseases such as Parkinson’s disease (PD) and Alzheimer’s disease (AD) are characterized by the accumulation of abnormal protein aggregates within the neurons (Ciechanover and Kwon, 2015; Sulistio and Heese, 2016). One of the major mechanisms by which the neuron removes abnormal proteins is the ubiquitin proteasome pathway (UPP) (Huang and Figueiredo-Pereira, 2010; Schwartz and Ciechanover, 2009).…”

“…Proteasome activity is decreased in the brain of early phase AD patients (Keck et al, 2003; Keller et al, 2000; Lopez Salon et al, 2000; Sulistio and Heese, 2016). Downregulation of E1 and E2 enzymes and proteasome subunits have been detected in AD brains (Lopez Salon et al, 2000).…”

Proteotoxicity and Cardiac Dysfunction

“…For example, the UPS is compromised in both the neurodegenerative diseases 183 as well as in DRM. 154 Conceptually, it is rather straightforward to appreciate that large aggregates of ubiquitinated proteins may negatively impact on a subset of the cell's clearance pathways as they are trafficked to the proteasome but are too large to pass through the constraints of the proteasomal bore (Figure 1, panel 2).…”