Induction of the Immunoproteasome Subunit Lmp7 Links Proteostasis and Immunity in α-Synuclein Aggregation Disorders
Scott Ugras,
Malcolm J. Daniels,
Hossein Fazelinia,
Neal S. Gould,
Anastasia K. Yocum,
Kelvin C. Luk,
Esteban Luna,
Hua Ding,
Chris McKennan,
Steven Seeholzer,
Dan Martinez,
Perry Evans,
Daniel Brown,
John E. Duda,
Harry Ischiropoulos
Affiliations
Scott Ugras
Biochemistry and Molecular Biophysics Graduate Group, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
Malcolm J. Daniels
Pharmacology Graduate Group, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
Hossein Fazelinia
Children's Hospital of Philadelphia Research Institute, Philadelphia, PA 19104, USA
Neal S. Gould
Children's Hospital of Philadelphia Research Institute, Philadelphia, PA 19104, USA
Anastasia K. Yocum
A2IDEA, LLC, Ann Arbor, MI 48105, USA
Kelvin C. Luk
Center for Neurodegenerative Disease Research, Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
Esteban Luna
Center for Neurodegenerative Disease Research, Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
Hua Ding
Children's Hospital of Philadelphia Research Institute, Philadelphia, PA 19104, USA
Chris McKennan
Children's Hospital of Philadelphia Research Institute, Philadelphia, PA 19104, USA; Department of Statistics, University of Chicago, 60637, USA
Steven Seeholzer
Children's Hospital of Philadelphia Research Institute, Philadelphia, PA 19104, USA
Dan Martinez
Children's Hospital of Philadelphia Research Institute, Philadelphia, PA 19104, USA
Perry Evans
Department of Biomedical and Health Informatics, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA
Daniel Brown
Parkinson's Disease Research, Education and Clinical Center, Michael J. Crescenz VA Medical Center, USA; Department of Neurosurgery, Perelman School of Medicine, University of Pennsylvania, USA
John E. Duda
Parkinson's Disease Research, Education and Clinical Center, Michael J. Crescenz VA Medical Center, USA; Neurology, Perelman School of Medicine, University of Pennsylvania, USA
Harry Ischiropoulos
Biochemistry and Molecular Biophysics Graduate Group, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Children's Hospital of Philadelphia Research Institute, Philadelphia, PA 19104, USA; Center for Neurodegenerative Disease Research, Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Department of Pediatrics, Children's Hospital of Philadelphia Research Institute and Department of Systems Pharmacology and Translational Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Corresponding author at: Department of Pediatrics, Children's Hospital of Philadelphia Research Institute, Philadelphia, PA 19104, USA.
Accumulation of aggregated α-synuclein into Lewy bodies is thought to contribute to the onset and progression of dopaminergic neuron degeneration in Parkinson's disease (PD) and related disorders. Although protein aggregation is associated with perturbation of proteostasis, how α-synuclein aggregation affects the brain proteome and signaling remains uncertain. In a mouse model of α-synuclein aggregation, 6% of 6215 proteins and 1.6% of 8183 phosphopeptides changed in abundance, indicating conservation of proteostasis and phosphorylation signaling. The proteomic analysis confirmed changes in abundance of proteins that regulate dopamine synthesis and transport, synaptic activity and integrity, and unearthed changes in mRNA binding, processing and protein translation. Phosphorylation signaling changes centered on axonal and synaptic cytoskeletal organization and structural integrity. Proteostatic responses included a significant increase in the levels of Lmp7, a component of the immunoproteasome. Increased Lmp7 levels and activity were also quantified in postmortem human brains with PD and dementia with Lewy bodies. Functionally, the immunoproteasome degrades α-synuclein aggregates and generates potentially antigenic peptides. Expression and activity of the immunoproteasome may represent testable targets to induce adaptive responses that maintain proteome integrity and modulate immune responses in protein aggregation disorders. Keywords: Neurodegeneration, Parkinson's disease, Dopaminergic neurons, Immunoproteasome, Proteostasis
