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Martin I.,Johns Hopkins University | Martin I.,Adrienne Helis Malvin Medical Research Foundation | Kim J.W.,Johns Hopkins University | Kim J.W.,Adrienne Helis Malvin Medical Research Foundation | And 22 more authors.
Cell | Year: 2014

Mutations in leucine-rich repeat kinase 2 (LRRK2) are a common cause of familial and sporadic Parkinson's disease (PD). Elevated LRRK2 kinase activity and neurodegeneration are linked, but the phosphosubstrate that connects LRRK2 kinase activity to neurodegeneration is not known. Here, we show that ribosomal protein s15 is a key pathogenic LRRK2 substrate in Drosophila and human neuron PD models. Phosphodeficient s15 carrying a threonine 136 to alanine substitution rescues dopamine neuron degeneration and age-related locomotor deficits in G2019S LRRK2 transgenic Drosophila and substantially reduces G2019S LRRK2-mediated neurite loss and cell death in human dopamine and cortical neurons. Remarkably, pathogenic LRRK2 stimulates both cap-dependent and cap-independent mRNA translation and induces a bulk increase in protein synthesis in Drosophila, which can be prevented by phosphodeficient T136A s15. These results reveal a novel mechanism of PD pathogenesis linked to elevated LRRK2 kinase activity and aberrant protein synthesis in vivo. © 2014 Elsevier Inc.


Martin I.,Johns Hopkins University | Kim J.W.,Johns Hopkins University | Dawson V.L.,Johns Hopkins University | Dawson V.L.,Adrienne Helis Malvin Medical Research Foundation | And 3 more authors.
Journal of Neurochemistry | Year: 2014

Mutations in the catalytic Roc-COR and kinase domains of leucine-rich repeat kinase 2 (LRRK2) are a common cause of familial Parkinson's disease (PD). LRRK2 mutations cause PD with age-related penetrance and clinical features identical to late-onset sporadic PD. Biochemical studies support an increase in LRRK2 kinase activity and a decrease in GTPase activity for kinase domain and Roc-COR mutations, respectively. Strong evidence exists that LRRK2 toxicity is kinase dependent leading to extensive efforts to identify selective and brain-permeable LRRK2 kinase inhibitors for clinical development. Cell and animal models of PD indicate that LRRK2 mutations affect vesicular trafficking, autophagy, protein synthesis, and cytoskeletal function. Although some of these biological functions are affected consistently by most diseaselinked mutations, others are not and it remains currently unclear how mutations that produce variable effects on LRRK2 biochemistry and function all commonly result in the degeneration and death of dopamine neurons. LRRK2 is typically present in Lewy bodies and its toxicity in mammalian models appears to be dependent on the presence of a-synuclein, which is elevated in human iPS-derived dopamine neurons from patients harboring LRRK2 mutations. Here, we summarize biochemical and functional studies of LRRK2 and its mutations and focus on aberrant vesicular trafficking and protein synthesis as two leading mechanisms underlying LRRK2-linked disease. © 2014 International Society for Neurochemistry.


Mitsiades N.,Baylor College of Medicine | Sung C.C.,New York Medical College | Schultz N.,New York Medical College | Danila D.C.,New York Medical College | And 9 more authors.
Cancer Research | Year: 2012

Androgen receptor (AR) signaling persists in castration-resistant prostate carcinomas (CRPC), because of several mechanisms that include increased AR expression and intratumoral androgen metabolism. We investigated the mechanisms underlying aberrant expression of transcripts involved in androgen metabolism in CRPC. We compared gene expression profiles and DNA copy number alteration (CNA) data from 29 normal prostate tissue samples, 127 primary prostate carcinomas (PCa), and 19 metastatic PCas. Steroidogenic enzyme transcripts were evaluated by quantitative reverse transcriptase PCR in PCa cell lines and circulating tumor cells (CTC) from CRPC patients. Metastatic PCas expressed higher transcript levels for AR and several steroidogenic enzymes, including SRD5A1, SRD5A3, and AKR1C3, whereas expression of SRD5A2, CYP3A4, CYP3A5, and CYP3A7 was decreased. This aberrant expression was rarely associated with CNAs. Instead, our data suggest distinct patterns of coordinated aberrant enzyme expression. Inhibition of AR activity by itself stimulated AKR1C3 expression. The aberrant expression of the steroidogenic enzyme transcripts was detected in CTCs from CRPC patients. In conclusion, our findings identify substantial interpatient heterogeneity and distinct patterns of dysregulated expression of enzymes involved in intratumoral androgen metabolism in PCa. These steroidogenic enzymes represent targets for complete suppression of systemic and intratumoral androgen levels, an objective that is supported by the clinical efficacy of the CYP17 inhibitor abiraterone. A comprehensive AR axis-targeting approach via simultaneous, frontline enzymatic blockade, and/or transcriptional repression of several steroidogenic enzymes, in combination with GnRH analogs and potent antiandrogens, would represent a powerful future strategy for PCa management. ©2012 AACR.


Lee Y.,Johns Hopkins University | Dawson V.L.,Johns Hopkins University | Dawson V.L.,Adrienne Helis Malvin Medical Research Foundation | Dawson T.M.,Johns Hopkins University | Dawson T.M.,Adrienne Helis Malvin Medical Research Foundation
Cold Spring Harbor Perspectives in Medicine | Year: 2012

Parkinson's disease (PD) is a complex genetic disorder that is associated with environmental risk factors and aging. Vertebrate genetic models, especially mice, have aided the study of autosomal-dominant and autosomal-recessive PD. Mice are capable of showing a broad range of phenotypes and, coupled with their conserved genetic and anatomical structures, provide unparalleled molecular and pathological tools to model human disease. These models used in combination with aging and PD-associated toxins have expanded our understanding of PD pathogenesis. Attempts to refine PD animal models using conditional approaches have yielded in vivo nigrostriatal degeneration that is instructive in ordering pathogenic signaling and in developing therapeutic strategies to cure or halt the disease. Here, we provide an overview of the generation and characterization of transgenic and knockout mice used to study PD followed by a review of the molecular insights that have been gleaned from current PD mouse models. Finally, potential approaches to refine and improve current models are discussed. © 2012 Cold Spring Harbor Laboratory Press.


Kageyama Y.,Johns Hopkins University | Hoshijima M.,University of California at San Diego | Seo K.,Johns Hopkins University | Bedja D.,Johns Hopkins University | And 13 more authors.
EMBO Journal | Year: 2014

Mitochondrial dynamics and mitophagy have been linked to cardiovascular and neurodegenerative diseases. Here, we demonstrate that the mitochondrial division dynamin Drp1 and the Parkinson's disease-associated E3 ubiquitin ligase parkin synergistically maintain the integrity of mitochondrial structure and function in mouse heart and brain. Mice lacking cardiac Drp1 exhibited lethal heart defects. In Drp1KO cardiomyocytes, mitochondria increased their connectivity, accumulated ubiquitinated proteins, and decreased their respiration. In contrast to the current views of the role of parkin in ubiquitination of mitochondrial proteins, mitochondrial ubiquitination was independent of parkin in Drp1KO hearts, and simultaneous loss of Drp1 and parkin worsened cardiac defects. Drp1 and parkin also play synergistic roles in neuronal mitochondrial homeostasis and survival. Mitochondrial degradation was further decreased by combination of Drp1 and parkin deficiency, compared with their single loss. Thus, the physiological importance of parkin in mitochondrial homeostasis is revealed in the absence of mitochondrial division in mammals. Synopsis In vivo analysis reveals a synergistic role of mitochondrial fission protein Drp1 and Parkinson's disease-associated ligase parkin in the regulation of ubiquitination and degradation of mitochondria in the heart and brain. Mitochondria divide in cardiomyocytes. Drp1 deficiency causes mitochondrial dysfunction, lethal heart failure and neurodegeneration due to defects in mitophagy. Mitochondria enlarge and accumulate ubiquitinated outer membrane proteins and mitophagy adaptor protein p62 independently of parkin. Parkin is dispensable for mitochondrial respiration, heart function and neuronal survival in the presence of Drp1-regulated mitophagy. Simultaneous loss of Drp1 and parkin increases mitophagy defects. In vivo analysis reveals a synergistic role of mitochondrial fission protein Drp1 and Parkinson's disease-associated ligase parkin in the regulation of ubiquitination and degradation of mitochondria in the heart and brain. © 2014 The Authors.


Dawson T.M.,Johns Hopkins University | Dawson T.M.,Adrienne Helis Malvin Medical Research Foundation | Dawson V.L.,Johns Hopkins University | Dawson V.L.,Adrienne Helis Malvin Medical Research Foundation
Neurodegenerative Diseases | Year: 2014

Background: Parkinson's disease (PD) is a chronic progressive neurologic disorder, which affects approximately one million men and women in the US alone. PD represents a heterogeneous disorder with common clinical manifestations and, for the most part, common neuropathological findings. Objective: This short article reviews the role of the ubiquitin E3 ligase in sporadic PD. Methods: The role of parkin in sporadic PD was reviewed by querying PubMed. Results: Parkin is inactivated in sporadic PD via S-nitrosylation, oxidative and dopaminergic stress, and phosphorylation by the stress-activated kinase c-Abl, leading to the accumulation of AIMP2 and PARIS (ZNF746). Conclusion: Strategies aimed at maintaining parkin in a catalytically active state or interfering with the toxicity of AIMP2 and PARIS (ZNF746) offer new therapeutic opportunities. © 2013 S. Karger AG, Basel.


Xiong Y.,Johns Hopkins University | Dawson V.L.,Johns Hopkins University | Dawson V.L.,Adrienne Helis Malvin Medical Research Foundation | Dawson T.M.,Johns Hopkins University | Dawson T.M.,Adrienne Helis Malvin Medical Research Foundation
Biochemical Society Transactions | Year: 2012

Mutations in the LRRK2 (leucine-rich repeat kinase 2) gene are the most frequent genetic cause of PD (Parkinson's disease), and these mutations play important roles in sporadic PD. The LRRK2 protein contains GTPase and kinase domains and several protein-protein interaction domains. The kinase and GTPase activity of LRRK2 seem to be important in regulating LRRK2-dependent cellular signalling pathways. LRRK2's GTPase and kinase domains may reciprocally regulate each other to direct LRRK2's ultimate function. Although most LRRK2 investigations are centred on LRRK2's kinase activity, the present review focuses on the function of LRRK2's GTPase activity in LRRK2 physiology and pathophysiology. ©The Authors Journal compilation ©2012 Biochemical Society.


Scarffe L.A.,Johns Hopkins University | Scarffe L.A.,Adrienne Helis Malvin Medical Research Foundation | Stevens D.A.,Johns Hopkins University | Dawson V.L.,Johns Hopkins University | And 3 more authors.
Trends in Neurosciences | Year: 2014

Parkinson's disease (PD) is a progressive neurodegenerative disease that causes a debilitating movement disorder. Although most cases of PD appear to be sporadic, rare Mendelian forms have provided tremendous insight into disease pathogenesis. Accumulating evidence suggests that impaired mitochondria underpin PD pathology. In support of this theory, data from multiple PD models have linked Phosphatase and tensin homolog (PTEN)-induced putative kinase 1 (PINK1) and parkin, two recessive PD genes, in a common pathway impacting mitochondrial health, prompting a flurry of research to identify their mitochondrial targets. Recent work has focused on the role of PINK1 and parkin in mediating mitochondrial autophagy (mitophagy); however, emerging evidence casts parkin and PINK1 as key players in multiple domains of mitochondrial health and quality control. © 2014 Elsevier Ltd.

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