Ribosomal protein s15 phosphorylation mediates LRRK2 neurodegeneration in Parkinson's disease

Ian Martin; Jungwoo Wren Kim; Byoung Dae Lee; Ho Chul Kang; Jin-Chong Xu; Hao Jia; Jeannette Stankowski; Min-Sik Kim; Jun Zhong; Manoj Kumar; Shaida A Andrabi; Yulan Xiong; Dennis W Dickson; Zbigniew K Wszolek; Akhilesh Pandey; Ted M Dawson; Valina L Dawson

doi:10.1016/j.cell.2014.01.064

Ribosomal protein s15 phosphorylation mediates LRRK2 neurodegeneration in Parkinson's disease

Cell. 2014 Apr 10;157(2):472-485. doi: 10.1016/j.cell.2014.01.064.

Authors

Ian Martin¹, Jungwoo Wren Kim², Byoung Dae Lee³, Ho Chul Kang⁴, Jin-Chong Xu⁵, Hao Jia², Jeannette Stankowski¹, Min-Sik Kim⁶, Jun Zhong⁷, Manoj Kumar⁵, Shaida A Andrabi¹, Yulan Xiong⁵, Dennis W Dickson⁸, Zbigniew K Wszolek⁹, Akhilesh Pandey¹⁰, Ted M Dawson¹¹, Valina L Dawson¹²

Affiliations

¹ Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Adrienne Helis Malvin Medical Research Foundation, New Orleans, LA 70130, USA.
² Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Department of Physiology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Adrienne Helis Malvin Medical Research Foundation, New Orleans, LA 70130, USA.
³ Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Age-Related and Brain Disease Research Center, Department of Neuroscience, Kyung Hee University, Seoul 130-701, South Korea.
⁴ Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Department of Physiology, Ajou University School of Medicine, Suwon 443-749, South Korea.
⁵ Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
⁶ Department of Biological Chemistry, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; McKusick Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
⁷ McKusick Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
⁸ Department of Neuroscience, Mayo Clinic, Jacksonville, FL 32224, USA.
⁹ Department of Neurology, Mayo Clinic, Jacksonville, FL 32224, USA.
¹⁰ Department of Biological Chemistry, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; McKusick Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Adrienne Helis Malvin Medical Research Foundation, New Orleans, LA 70130, USA; Diana Helis Henry Medical Research Foundation, New Orleans, LA 70130, USA.
¹¹ Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Adrienne Helis Malvin Medical Research Foundation, New Orleans, LA 70130, USA. Electronic address: tdawson@jhmi.edu.
¹² Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Department of Physiology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Adrienne Helis Malvin Medical Research Foundation, New Orleans, LA 70130, USA. Electronic address: vdawson@jhmi.edu.

Abstract

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.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Amino Acid Sequence
Animals
Drosophila melanogaster
Humans
Leucine-Rich Repeat Serine-Threonine Protein Kinase-2
Molecular Sequence Data
Neurons / metabolism*
Neurons / pathology
Parkinson Disease / metabolism*
Parkinson Disease / pathology
Protein Serine-Threonine Kinases / metabolism*
Ribosomal Proteins / chemistry
Ribosomal Proteins / metabolism*

Substances

Ribosomal Proteins
ribosomal protein S15
LRRK2 protein, human
Leucine-Rich Repeat Serine-Threonine Protein Kinase-2
Protein Serine-Threonine Kinases

Abstract

Publication types

MeSH terms

Substances

Grants and funding