Amyloid peptides in different assembly states and related effects on isolated and cellular proteasomes

Sporadic inclusion-body myositis: Conformational multifactorial ageing-related degenerative muscle disease associated with proteasomal and lysosomal inhibition, endoplasmic reticulum stress, and accumulation of amyloid-β42 oligomers and phosphorylated tau

“…Decreased proteasome function has been recently reported in several neurodegenerative diseases characterized by accumulation of multiprotein aggregates in the brain [22,128,129]. AbPP/Ab have been reported to inhibit proteasomal activity in our culture IBM model and in other cells [129][130][131]. In s-IBM muscle fibers, we have demonstrated reduced activities of the three major proteasomal proteolytic enzymes [20].…”

“…In s-IBM muscle fibers, we have demonstrated reduced activities of the three major proteasomal proteolytic enzymes [20]. Several factors, in addition to increased AbPP and Ab, present in s-IBM muscle fibers might contribute to inhibiting proteasome function, including an ageing muscle fiber environment; protein over-crowding; oxidative stress [5,6,11], and accumulated ptau [5,6,11], a-synuclein [108], and UBB +1 [132] -all of these are capable of inhibiting proteasome activity in other systems [130,131,[133][134][135]. We propose that the ageing cellular environment of s-IBM muscle fibers, combined with factors such as oxidative stress and perhaps other detrimental molecular events, leads to abnormal production and accumulation of UBB +1 [132].…”

Impaired Autophagy in Sporadic Inclusion-Body Myositis and in Endoplasmic Reticulum Stress-Provoked Cultured Human Muscle Fibers

“…Moreover, both A␤PP and A␤ have been shown to inhibit proteasome. 8,65,66 In summary, we propose that a double impairment of protein disposal, caused by inhibition of both lysosomal and proteasomal degradation, contributes importantly to s-IBM pathogenesis. Although the igniting mechanisms leading to the s-IBM muscle fiber degeneration are still not known, our studies suggest that attempts to unblock protein degradation might be a therapeutic strategy for patients with s-IBM.…”

Sublethal Doses of β-Amyloid Peptide Abrogate DNA-dependent Protein Kinase Activity

“…Accordingly, we showed that down-regulation of DNA-PKcs protein is paralleled by A␤(25-35)-induced protein carbonylation, an irreversible and not repairable oxidative protein modification, which may render proteins more prone to proteolytic degradation by proteasomes (79,80). Although it is well known that A␤ oligomers and fibrils can inhibit the proteasome activity (81,82), it has been demonstrated that soluble A␤(1-40) is able to induce the degradation of post-synaptic density-95, specifically by proteasomes (83). In addition, naturally secreted A␤ oligomers cause the reduction of neuronal EphB2 protein, and coincubation with lactacystin, a specific proteasome inhibitor, rescues this effect with a concomitant increase of ubiquitinated EphB2 (84).…”