Parkin Substrates

Vesicular trafficking and inclusion body formation are both dependent on the integrity of microtubules and other cytoskeletal components. Parkin has been shown to target misfolded tubulin for degradation [251] (figure 4.6B) and to interact with centrosomes upon proteasomal inhibition [252]. Whether this reflects association with specific substrates or co-localization with proteasomes in centrosomes re- 

Parkin substrates. (B) A model for Parkin-dependent degradation of misfolded proteins. Parkin recruits a complex containing molecular chaperones and the unfolded substrates to the proteasome. Degradation may be facilitated by 

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CoRTi, O., et al.. The p38 subunit of the aminoacyl-tRNA synthetase complex is a Parkin substrate linking protein biosynthesis and neurodegeneration. Hum Mol Genet, 2003, 12(12), 1427-37. 

In model-1 (Fig. 1), which provides the mechanism of AR-JP, cumulative increases of a putative parkin substrate(s), provisionally termed X(s), which has yet to be identified, cause selective neuronal death. In this model, the target X protein is simply considered as a factor whose accumulation directly mediates death of dopaminergic neurons i.e., abnormal accumulation of X forcibly evokes cell death. To explain that genetic defect of the parkin gene causes specifically dopaminergic neuronal... 

Corti O, Hampe C, Koutnikova H, Darios F, Jacquier S, Prigent A, Robinson JC, Pradier L, Ruberg M, Mirande M, Hirsch E, Rooney T, Fournier A, Brice A (2003) The p38 subunit of the aminoacyl-tRNA synthetase complex is a Parkin substrate Unking protein biosynthesis and neurodegeneration. Hum Mol Genet 12 1427-1437 Couzin J (2008) Genetics. Once shunned, test for Alzheimer s risk headed to market. Science 319 1022-1023... 

Mitochondrial dynamics (fission, fusion, migration) has been reported to play an important role in neurotransmission, synaptic stability, and maintenance and neuronal survival. PBMKl and Parkin are closely associated within the regulation of mitochondrial dynamics and function (Bueler, 2009). Mutations in DJ-1, Parkin, and PINK 1 render animals more susceptible to oxidative stress and mitochondrial toxins implicated in sporadic PD. DJ-1, Parkin, and PINKl form a complex (termed PPD complex) to promote ubiquitination and degradation of Parkin substrates, including Parkin itself and synphilin-1. In addition, mutant proteins may retard the transport of nuclear-encoded mitochondrial proteins to mitochondria, interact with mitochondrial proteins and disrupt the electron transport chain, induce free radicals, cause... 

Imai, Y., et al.. An unfolded putative transmembrane polypeptide, which can lead to endoplasmic reticulum stress, is a substrate of Parkin. Cell, 2001, 105(7), 891-902. 

Parkinson s disease Parkin (E3, ubiquitin iigase) UCH-L1 a-Synuciein (substrate) 431- -433... 

Figure 1. Model-1. Loss-of-function of parkin specifically causes AR-JP. Ub, ubiquitin SN, substantia nigra AR-JP, autosomal recessive juvenile parkinsonism. X(s) is a SN-specific substrate(s) whose accumulation in non-ubiquitinated form could activate directly the cell death pathway.

Physiologically, X may contribute to the removal of dopaminergic neuronal cells, when they are accidentally impaired. If so, why does parkin exist in other types of cells and tissues Probably, in these cells parkin targets a different substrate(s), termed here Y(s) , which is distinct from X for cell death-signalling. In addition, another unknown Ub-protein ligase(s) may be responsible for ubiquitinating Y and thus in AR-JP no appreciable defects... 

In this review, we proposed two models in AR-JP model-1 for the function of parkin whose dysfunction causes AR-JP (Fig. 1) and modeI-2, which hypothesizes that AR-JP is an alternative form of sporadic PD (Fig. 2). In model-1, we predict that parkin target X is a factor whose accumulation can activate the death-signalling pathway, which is only present in dopaminergic neurons, as a sequence to reduced E3-function of parkin. In contrast, in model-2, we predict that parkin is a member of the quality-controlling E3 family and is involved in the LB formation. At present, we do not know which model is correct, but we favor the latter scenario shown in model-2, because the presence of SN-specific substrate X seems unlikely and it is plausible that parkin is present in LB. However, to date many neuropathologists follow the former model-1 and believe that AR-JP differs from sporadic PD based on pathological evidence, i.e., LB must be detected at postmortem examination in the surviving neurons of PD. 

Maillacheruvu, K.Y., and Parkin, GF. (1996) Kinetics of growth, substrate utilization and sulfide toxicity for proprionate, acetate, and hydrogen utilizers in anaerobic systems. Water Environ. Res. 68, 1099-1106. 

Shaw, G. A., Parkin, I. P. and WiUiams, D. E. (2003) Atmospheric pressure chemical vapour deposition of Cr2-xTix03 (CTO) thin films on to gas sensing substrates. Journal of Materials Chemistry 13,2957-62. 

Page C, Wilson M, Mordan N, Chizanowski W, Knowles P, Parkin PI. Study of the adhesion of Staphylococcus aureus to coated glass substrates. J Mater Sci 2010 46 6355-63. 

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