Sathya R Sriram

Johns Hopkins University, Baltimore, MD, United States

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Publications (4)19.25 Total impact

  • Sathya R. Sriram, Valina L. Dawson, Ted M. Dawson
    Protein Degradation Series: 4 Volume Set, 12/2007: pages 211 - 236; , ISBN: 9783527619320
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    ABSTRACT: Aminoacyl-tRNA synthetase-interacting multifunctional protein type 2 was recently identified as an authentic substrate of the ubiquitin E3 ligase, parkin, a gene associated with autosomal recessive juvenile parkinsonism. Far upstream element-binding protein 1 is known to be degraded in an aminoacyl-tRNA synthetase interacting multifunctional protein type 2 dependent manner, which is crucial for lung cell maturation in early development. Therefore, we wondered whether far upstream element-binding protein 1 levels are altered in the absence of Parkin and in Parkinson disease. We herein report that far upstream element-binding protein 1 accumulates in Parkin knock-out mice, patients with autosomal recessive juvenile parkinsonism, sporadic Parkinson disease, and diffuse Lewy Body disease as well as the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine mouse model of Parkinson disease. Moreover, Parkin interacts with and ubiquitinates far upstream element-binding protein 1 facilitating its degradation through the ubiquitin proteasome system. Taken together, these results suggest that far upstream element-binding protein 1 is an authentic substrate of Parkin and that far upstream element-binding protein 1 might play an important role in development of Parkinson disease pathology along with aminoacyl-tRNA synthetase interacting multifunctional protein type 2.
    Journal of Biological Chemistry 07/2006; 281(24):16193-6. · 4.65 Impact Factor
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    ABSTRACT: Mutations in parkin are largely associated with autosomal recessive juvenile parkinsonism. The underlying mechanism of pathogenesis in parkin-associated Parkinson's disease (PD) is thought to be due to the loss of parkin's E3 ubiquitin ligase activity. A subset of missense and nonsense point mutations in parkin that span the entire gene and represent the numerous inheritance patterns that are associated with parkin-linked PD were investigated for their E3 ligase activity, localization and their ability to bind, ubiquitinate and effect the degradation of two substrates, synphilin-1 and aminoacyl-tRNA synthetase complex cofactor, p38. Parkin mutants vary in their intracellular localization, binding to substrates and enzymatic activity, yet they are ultimately deficient in their ability to degrade substrate. These results suggest that not all parkin mutations result in loss of parkin's E3 ligase activity, but they all appear to manifest as loss-of-function mutants due to defects in solubility, aggregation, enzymatic activity or targeting proteins to the proteasome for degradation.
    Human Molecular Genetics 10/2005; 14(17):2571-86. · 7.69 Impact Factor
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    ABSTRACT: Autosomal-recessive juvenile parkinsonism (AR-JP) is caused by loss-of-function mutations of the parkin gene. Parkin, a RING-type E3 ubiquitin ligase, is responsible for the ubiquitination and degradation of substrate proteins that are important in the survival of dopamine neurons in Parkinson's disease (PD). Accordingly, the abnormal accumulation of neurotoxic parkin substrates attributable to loss of parkin function may be the cause of neurodegeneration in parkin-related parkinsonism. We evaluated the known parkin substrates identified to date in parkin null mice to determine whether the absence of parkin results in accumulation of these substrates. Here we show that only the aminoacyl-tRNA synthetase cofactor p38 is upregulated in the ventral midbrain/hindbrain of both young and old parkin null mice. Consistent with upregulation in parkin knock-out mice, brains of AR-JP and idiopathic PD and diffuse Lewy body disease also exhibit increased level of p38. In addition, p38 interacts with parkin and parkin ubiquitinates and targets p38 for degradation. Furthermore, overexpression of p38 induces cell death that increases with tumor necrosis factor-alpha treatment and parkin blocks the pro-cell death effect of p38, whereas the R42P, familial-linked mutant of parkin, fails to rescue cell death. We further show that adenovirus-mediated overexpression of p38 in the substantia nigra in mice leads to loss of dopaminergic neurons. Together, our study represents a major advance in our understanding of parkin function, because it clearly identifies p38 as an important authentic pathophysiologic substrate of parkin. Moreover, these results have important implications for understanding the molecular mechanisms of neurodegeneration in PD.
    Journal of Neuroscience 09/2005; 25(35):7968-78. · 6.91 Impact Factor

Publication Stats

293 Citations
19.25 Total Impact Points

Institutions

  • 2005–2007
    • Johns Hopkins University
      • Department of Neurology
      Baltimore, MD, United States
    • Institute for Molecular Medicine and Cell Therapy
      Düsseldorf, North Rhine-Westphalia, Germany