Mechanisms of aluminium neurotoxicity in oxidative stress-induced ...
Mechanisms of aluminium neurotoxicity in oxidative stress-induced ... Mechanisms of aluminium neurotoxicity in oxidative stress-induced ...
INTRODUCTION Figure 18: The ubiquitin-proteasome system (A) and possible sites where different forms of PD might interfere with the UPS (B) (Olanow and McNaught 2006) 34 The discovery of ubiquitin as a major constituent of LB (Kuzuhara et al. 1988) was the first evidence that suggest the involvement of the ubiquitin-proteasome system (UPS) dysfunction in the pathogenesis of PD. This was later supported by the identification of parkin mutations associated with young onset autosomal recessive PD (Kitada at al. 1988). The UPS is the major mechanism used to degrade abnormal proteins, or proteins at the ends of their life cycles. Misfolded or unwanted proteins targeted for degradation are covalently modified via polyubiquitination on lysine residues and directed to the proteasome. Three enzymes are required: ubiquitin- activating enzymes (E1), ubiquitin-conjugating enzymes (E2), and ubiquitin ligases
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. 35
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- Page 25 and 26: INTRODUCTION PARKINSON’S DISEASE
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INTRODUCTION<br />
Figure 18: The ubiquit<strong>in</strong>-proteasome system (A) and possible sites where different forms <strong>of</strong> PD might<br />
<strong>in</strong>terfere with the UPS (B) (Olanow and McNaught 2006)<br />
34<br />
The discovery <strong>of</strong> ubiquit<strong>in</strong> as a major constituent <strong>of</strong> LB (Kuzuhara et al. 1988)<br />
was the first evidence that suggest the <strong>in</strong>volvement <strong>of</strong> the ubiquit<strong>in</strong>-proteasome system<br />
(UPS) dysfunction <strong>in</strong> the pathogenesis <strong>of</strong> PD. This was later supported by the<br />
identification <strong>of</strong> park<strong>in</strong> mutations associated with young onset autosomal recessive PD<br />
(Kitada at al. 1988). The UPS is the major mechanism used to degrade abnormal<br />
prote<strong>in</strong>s, or prote<strong>in</strong>s at the ends <strong>of</strong> their life cycles. Misfolded or unwanted prote<strong>in</strong>s<br />
targeted for degradation are covalently modified via polyubiquit<strong>in</strong>ation on lys<strong>in</strong>e<br />
residues and directed to the proteasome. Three enzymes are required: ubiquit<strong>in</strong>-<br />
activat<strong>in</strong>g enzymes (E1), ubiquit<strong>in</strong>-conjugat<strong>in</strong>g enzymes (E2), and ubiquit<strong>in</strong> ligases