title: Overexpression of the calpain-specific inhibitor calpastatin reduces human alpha-Synuclein processing, aggregation and synaptic impairment in [A30P]αSyn transgenic mice.
abstract: Lewy bodies, a pathological hallmark of Parkinson's disease (PD), contain aggregated alpha-synuclein (αSyn), which is found in several modified forms and can be discovered phosphorylated, ubiquitinated and truncated. Aggregation-prone truncated species of αSyn caused by aberrant cleavage of this fibrillogenic protein are hypothesized to participate in its sequestration into inclusions subsequently leading to synaptic dysfunction and neuronal death. Here, we investigated the role of calpain cleavage of αSyn in vivo by generating two opposing mouse models. We crossed into human [A30P]αSyn transgenic (i) mice deficient for calpastatin, a calpain-specific inhibitor, thus enhancing calpain activity (SynCAST(-)) and (ii) mice overexpressing human calpastatin leading to reduced calpain activity (SynCAST(+)). As anticipated, a reduced calpain activity led to a decreased number of αSyn-positive aggregates, whereas loss of calpastatin led to increased truncation of αSyn in SynCAST(-). Furthermore, overexpression of calpastatin decreased astrogliosis and the calpain-dependent degradation of synaptic proteins, potentially ameliorating the observed neuropathology in [A30P]αSyn and SynCAST(+) mice. Overall, our data further support a crucial role of calpains, particularly of calpain 1, in the pathogenesis of PD and in disease-associated aggregation of αSyn, indicating a therapeutic potential of calpain inhibition in PD.
authors.affiliation: Institute of Medical Genetics and Applied Genomics, University of Tuebingen, Tuebingen 72076, Germany.
authors.forename: Meike
authors.initials: M
authors.lastname: Diepenbroek
authors.affiliation: Institute of Medical Genetics and Applied Genomics, University of Tuebingen, Tuebingen 72076, Germany.
authors.forename: Nicolas
authors.initials: N
authors.lastname: Casadei
authors.affiliation: Institute of Medical Genetics and Applied Genomics, University of Tuebingen, Tuebingen 72076, Germany.
authors.forename: Hakan
authors.initials: H
authors.lastname: Esmer
authors.affiliation: RIKEN Brain Science Institute, Laboratory for Proteolytic Neuroscience, Saitama 351-0198, Japan.
authors.forename: Takaomi C
authors.initials: TC
authors.lastname: Saido
authors.affiliation: RIKEN Brain Science Institute, Laboratory for Proteolytic Neuroscience, Saitama 351-0198, Japan.
authors.forename: Jiro
authors.initials: J
authors.lastname: Takano
authors.affiliation: Department of Neurodegeneration, Hertie Institute for Clinical Brain Research, University Clinics Tübingen, 72076 Tuebingen, Germany.
authors.forename: Philipp J
authors.initials: PJ
authors.lastname: Kahle
authors.affiliation: Center for Dementia Research, Nathan S. Kline Institute, 140 Old Orangeburg Road, Orangeburg, NY 10962, USA.
authors.forename: Ralph A
authors.initials: RA
authors.lastname: Nixon
authors.affiliation: Center for Dementia Research, Nathan S. Kline Institute, 140 Old Orangeburg Road, Orangeburg, NY 10962, USA.
authors.forename: Mala V
authors.initials: MV
authors.lastname: Rao
authors.affiliation: Laboratoire d'Enzymologie et Biochimie Structurales, Centre National de la Recherche Scientifique, 91198 Gif-sur-Yvette, France.
authors.forename: Ronald
authors.initials: R
authors.lastname: Melki
authors.affiliation: Laboratoire d'Enzymologie et Biochimie Structurales, Centre National de la Recherche Scientifique, 91198 Gif-sur-Yvette, France.
authors.forename: Laura
authors.initials: L
authors.lastname: Pieri
authors.affiliation: Functional Proteomics, Medizinisches Proteom-Center, Ruhr-University Bochum, 44780 Bochum, Germany and.
authors.forename: Stefan
authors.initials: S
authors.lastname: Helling
authors.affiliation: Functional Proteomics, Medizinisches Proteom-Center, Ruhr-University Bochum, 44780 Bochum, Germany and.
authors.forename: Katrin
authors.initials: K
authors.lastname: Marcus
authors.affiliation: Department of Neurodegeneration, Hertie Institute for Clinical Brain Research, University Clinics Tübingen, 72076 Tuebingen, Germany.
authors.forename: Rejko
authors.initials: R
authors.lastname: Krueger
authors.affiliation: Department of Pathology and Department of Neurosciences, University of California-San Diego, 9500 Gilman Drive, La Jolla, CA 92003-0624, USA.
authors.forename: Eliezer
authors.initials: E
authors.lastname: Masliah
authors.affiliation: Institute of Medical Genetics and Applied Genomics, University of Tuebingen, Tuebingen 72076, Germany, olaf.riess@med.uni-tuebingen.de snuber@ucsd.edu.
authors.forename: Olaf
authors.initials: O
authors.lastname: Riess
authors.affiliation: Institute of Medical Genetics and Applied Genomics, University of Tuebingen, Tuebingen 72076, Germany, Department of Neurosciences, University of California-San Diego, 9500 Gilman Drive, La Jolla, CA 92003-0624, USA olaf.riess@med.uni-tuebingen.de snuber@ucsd.edu.
authors.forename: Silke
authors.initials: S
authors.lastname: Nuber
mesh_terms: D000818:Animals; D002135:Calcium-Binding Proteins / Q000235:genetics* / Q000378:metabolism; D002154:Calpain / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D004195:Disease Models, Animal; D005786:Gene Expression Regulation; D006801:Humans; D016631:Lewy Bodies / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008822:Mice, Transgenic; D009474:Neurons / Q000378:metabolism / Q000473:pathology; D010300:Parkinson Disease / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D066329:Protein Aggregates; D066263:Protein Aggregation, Pathological / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D059748:Proteolysis; D015398:Signal Transduction; D013569:Synapses / Q000378:metabolism / Q000473:pathology; D051844:alpha-Synuclein / Q000235:genetics* / Q000378:metabolism
chemical_list: D002135:Calcium-Binding Proteins; D066329:Protein Aggregates; C497605:Snca protein, mouse; D051844:alpha-Synuclein; C033668:calpastatin; D002154:Calpain; C112682:Capn1 protein, mouse