Disrupted proteasome function

The mechanism by which the mutated a-synuclein produces toxicity is not clear, but it is thought that the mutated protein forms fibrils, and the oligomers or fibrils formed from this protein exert a toxic gain of function leading to disruption of proteasomal function and the formation of Lewy bodies. However, as evidenced by the... 

Different mechanisms have been described to explain the toxic effects of PrP in the cytosolic compartment. In one study co-aggregation of misfolded cytoPrP with the anti-apoptotic protein Bcl-2 was shown to coincide with toxicity [71]. Another study reported that cytoPrP can interact with the E3 ubiquitin ligase Mahogunin, thereby disrupting its function [67]. Interestingly, a toxic potential was also observed for cytosolically localized PrPSc, which can inhibit proteasomal activity [69]. 

Fig. 10 Model of glutamate receptor Internalization through Ap-mediated activation of STEP. Ap activates the a7 nicotinic receptor, leading to Ca + influx and activation of calcineurin [197], Calcineurin subsequently dephosphorylates and activates STEP. Concomitantly, Ap also elevates STEP protein levels through inhibition of the ubiquitin proteasome system [203]. STEP dephosphorylates a regulatory tyrosine residue in both the NR2B and GluR2 glutamate receptor subunits, leading to internalization of the receptors [199,200]. As a result, synaptic function is disrupted (Figure from ref. 131, with permission)...

Another important finding is that many neurodegenerative diseases are characterized by aberrant protein phosphorylation and ubiquitination (Thomas et al., 2009). Thus, disruption of the phosphorylation of neurotransmitter receptors and hyperphosphorylation of t-protein has been implicated in impaired memory function in AD. Similarly, AD also involves aberrant accumulation of proteins that are normally degraded by the ubiquitin-proteasome system. It is suggested that phosphorylation and ubiquitination of proteins can serve biomarkers for neurodegenerative diseases (Thomas et al., 2009). 

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