Mechanisms of aluminium neurotoxicity in oxidative stress-induced ...

INTRODUCTION
(E3) (Figure 18A). Loss-of-function mutations in parkin, an E3 ubiquitin ligase, abolish
its activity leading to proteasomal dysfunction and subsequent accumulation of
aggregated proteins (Cookson 2005, Yang et al. 2009). Parkin was also shown to
interact with PINK1 (PARK6 gene) and DJ-1 (PARK7 gene) (Shiba et al. 2009, Um et
al. 2009). These three PD-related proteins physically interact and form a functional E3
ligase complex to regulate UPS-mediated protein degradation (Xiong et al. 2009). The
role of the UPS in neurodegeneration was also enhanced with the identification of
mutation I93M in UCH-L1 (Leroy et al. 1998) in autosomal recessive PD. The UCH-L1
protein is a de-ubiquitinating enzyme, it cleaves ubiquitin from the ubiquitin-protein
adduct enhabling the protein to enter the proteasome. UCH-L1 mutations may prejudice
proteasomal degradation and also lower the availability of ubiquitin monomers required
for the removal of additional misfolded proteins. Some studies demonstrated another
mutation within this gene (S18Y) that decreases risk for PD, but this remains
controversial (Maraganore et al. 2004, Healy et al. 2006). In brief, when a component of
the UPS required for degrading proteins is altered or the capacity of UPS has been
exceeded as an outcome of the excessive production of misfolded proteins, or a
combination of both, proteolytic stress happens (Figure 18B, Olanow 2007). This leads
to the accumulation and aggregation of proteins with subsequent damage in a wide
range of cellular functions and apoptosis.
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