Chung, K. K., Zhang, Y., Lim, K. L., Tanaka, Y., Huang, H., Gao, J. et al. Parkin ubiquitinates the a-synuclein interacting protein, synphilin-1, implications for Lewy-body formation in Parkinson disease. Nat. Med. 7, 1144-1150

Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
Nature Medicine (Impact Factor: 27.36). 11/2001; 7(10). DOI: 10.1038/nm1001-1144
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Parkinson disease is a common neurodegenerative disorder characterized by the loss of dopaminergic neurons and the presence of intracytoplasmic-ubiquitinated inclusions (Lewy bodies). Mutations in alpha-synuclein (A53T, A30P) and parkin cause familial Parkinson disease. Both these proteins are found in Lewy bodies. The absence of Lewy bodies in patients with parkin mutations suggests that parkin might be required for the formation of Lewy bodies. Here we show that parkin interacts with and ubiquitinates the alpha-synuclein-interacting protein, synphilin-1. Co-expression of alpha-synuclein, synphilin-1 and parkin result in the formation of Lewy-body-like ubiquitin-positive cytosolic inclusions. We further show that familial-linked mutations in parkin disrupt the ubiquitination of synphilin-1 and the formation of the ubiquitin-positive inclusions. These results provide a molecular basis for the ubiquitination of Lewy-body-associated proteins and link parkin and alpha-synuclein in a common pathogenic mechanism through their interaction with synphilin-1.

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Available from: Kah-Leong Lim, Mar 07, 2014
    • "However, in aging and disease, these systems fail to repair or destroy abnormal polypeptides, which then tend to form small cytoplasmic aggregates that cause cell toxicity, leading to various protein misfolding disorders (Sherman & Goldberg, 2001; Meriin & Sherman, 2005). A special cellular machinery has evolved to transport such aggregates to the centrosome, forming an organelle called the aggresome (Johnston et al, 1998; Chung et al, 2001; Webb et al, 2004; Corboy et al, 2005). The aggresome serves as a storage compartment for protein aggregates and may be actively involved in their refolding and proteasomal or autophagic degradation. "
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    ABSTRACT: The aggresome is an organelle that recruits aggregated proteins for storage and degradation. We performed an siRNA screen for proteins involved in aggresome formation and identified novel mammalian AAA+ protein disaggregases RuvbL1 and RuvbL2. Depletion of RuvbL1 or RuvbL2 suppressed aggresome formation and caused buildup of multiple cytoplasmic aggregates. Similarly, downregulation of RuvbL orthologs in yeast suppressed the formation of an aggresome-like body and enhanced the aggregate toxicity. In contrast, their overproduction enhanced the resistance to proteotoxic stress independently of chaperone Hsp104. Mammalian RuvbL associated with the aggresome, and the aggresome substrate synphilin-1 interacted directly with the RuvbL1 barrel-like structure near the opening of the central channel. Importantly, polypeptides with unfolded structures and amyloid fibrils stimulated the ATPase activity of RuvbL. Finally, disassembly of protein aggregates was promoted by RuvbL. These data indicate that RuvbL complexes serve as chaperones in protein disaggregation.
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    • "We acknowledge that there are many differences between a cell culture model and what may be seen in a culture dish. One operating assumption is that loss of PARK2 may lead to reduced processing of SNCA-associated proteins in particular SYNPHILIN; other data suggest that it is a nonclassical pathway (Chung et al., 2001; Lim et al., 2005; Sherer et al., 2003b; Zhang et al., 2013). We believe that altered ratios of interacting proteins may lead to either an increase or decrease depending on the stage of the disease. "
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    ABSTRACT: In this study, we used patient-specific and isogenic PARK2-induced pluripotent stem cells (iPSCs) to show that mutations in PARK2 alter neuronal proliferation. The percentage of TH(+) neurons was decreased in Parkinson's disease (PD) patient-derived neurons carrying various mutations in PARK2 compared with an age-matched control subject. This reduction was accompanied by alterations in mitochondrial:cell volume fraction (mitochondrial volume fraction). The same phenotype was confirmed in isogenic PARK2 null lines. The mitochondrial phenotype was also seen in non-midbrain neurons differentiated from the PARK2 null line, as was the functional phenotype of reduced proliferation in culture. Whole genome expression profiling at various stages of differentiation confirmed the mitochondrial phenotype and identified pathways altered by PARK2 dysfunction that include PD-related genes. Our results are consistent with current model of PARK2 function where damaged mitochondria are targeted for degradation via a PARK2/PINK1-mediated mechanism. Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.
    Full-text · Article · Apr 2015 · Stem Cell Reports
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    • "Synphilin-1 has been reported to interact with a number of proteins including alpha-synuclein, parkin and other proteasome/ubiquitin associated proteins [1]–[5]. Previous reports showed that synphilin-1 enhances the formation of intracellular protein inclusions and may be involved in Parkinson’s disease (PD) pathogenesis [1]–[4], [6]. Synphilin-1 can reduce PD-linked mutant alpha-synuclein-, rotenone-, and 6-HODA-induced toxicity in vitro and delays alpha-synucleinopathies in a PD mouse model in vivo [7], [8]. "
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    ABSTRACT: Synphilin-1 is a cytoplasmic protein that has been shown to be involved in the control of energy balance. Previously, we reported on the generation of a human synphilin-1 transgenic mouse model (SP1), in which overexpression of human synphilin-1 resulted in hyperphagia and obesity. Here, behavioral measures in SP1 mice were compared with those of their age-matched controls (NTg) at two time points: when there was not yet a group body weight difference ("pre-obese") and when SP1 mice were heavier ("obese"). At both time points, meal pattern analyses revealed that SP1 mice displayed higher daily chow intake than non-transgenic control mice. Furthermore, there was an increase in meal size in SP1 mice compared with NTg control mice at the obese stage. In contrast, there was no meal number change between SP1 and NTg control mice. In a brief-access taste procedure, both "pre-obese" and "obese" SP1 mice displayed concentration-dependent licking across a sucrose concentration range similar to their NTg controls. However, at the pre-obese stage, SP1 mice initiated significantly more trials to sucrose across the testing sessions and licked more vigorously at the highest concentration presented, than the NTg counterparts. These group differences in responsiveness to sucrose were no longer apparent in obese SP1 mice. These results suggest that at the pre-obese stage, the increased trials to sucrose in the SP1 mice reflects increased appetitive behavior to sucrose that may be indicative of the behavioral changes that may contribute to hyperphagia and development of obesity in SP1 mice. These studies provide new insight into synphilin-1 contributions to energy homeostasis.
    Full-text · Article · May 2014 · PLoS ONE
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