title: Alpha-synuclein-induced neurodegeneration is exacerbated in PINK1 knockout mice.
abstract: Loss-of-function mutations in the PINK1 gene lead to recessive forms of Parkinson's disease. Animal models with depleted PINK1 expression have failed to reproduce significant nigral dopaminergic neurodegeneration and clear alpha-synuclein pathology, main characteristics of the disease. In this study, we investigated whether alpha-synuclein pathology is altered in the absence of PINK1 in cell culture and in vivo. We observed that downregulation of PINK1 enhanced alpha-synuclein aggregation and apoptosis in a neuronal cell culture model for synucleinopathy. Silencing of PINK1 expression in mouse substantia nigra using recombinant adeno-associated viral vectors did not induce dopaminergic neurodegeneration in a long-term study up to 10 months, nor did it enhance or accelerate dopaminergic neurodegeneration after alpha-synuclein overexpression. However, in PINK1 knockout mice, overexpression of alpha-synuclein in the substantia nigra resulted in enhanced dopaminergic neurodegeneration as well as significantly higher levels of alpha-synuclein phosphorylation at serine 129 at 4 weeks postinjection. In conclusion, our results demonstrate that total loss of PINK1 leads to an increased sensitivity to alpha-synuclein-induced neuropathology and cell death in vivo.
authors.affiliation: Laboratory for Neurobiology and Gene Therapy, Department of Neurosciences, KU Leuven, Leuven, Belgium.
authors.forename: Marusela
authors.initials: M
authors.lastname: Oliveras-Salvá
authors.affiliation: Laboratory for Neurobiology and Gene Therapy, Department of Neurosciences, KU Leuven, Leuven, Belgium.
authors.forename: Francesca
authors.initials: F
authors.lastname: Macchi
authors.affiliation: Laboratory for Neurobiology and Gene Therapy, Department of Neurosciences, KU Leuven, Leuven, Belgium.
authors.forename: Valérie
authors.initials: V
authors.lastname: Coessens
authors.affiliation: Laboratory of Biochemistry, Interdisciplinary Research Centre KU Leuven-Kortrijk, Kortrijk, Belgium.
authors.forename: Angélique
authors.initials: A
authors.lastname: Deleersnijder
authors.affiliation: Laboratory of Biochemistry, Interdisciplinary Research Centre KU Leuven-Kortrijk, Kortrijk, Belgium.
authors.forename: Melanie
authors.initials: M
authors.lastname: Gérard
authors.affiliation: Laboratory for Neurobiology and Gene Therapy, Department of Neurosciences, KU Leuven, Leuven, Belgium.
authors.forename: Anke
authors.initials: A
authors.lastname: Van der Perren
authors.affiliation: Laboratory for Neurobiology and Gene Therapy, Department of Neurosciences, KU Leuven, Leuven, Belgium; Leuven Viral Vector Core, KU Leuven, Leuven, Belgium.
authors.forename: Chris
authors.initials: C
authors.lastname: Van den Haute
authors.affiliation: Laboratory for Neurobiology and Gene Therapy, Department of Neurosciences, KU Leuven, Leuven, Belgium. Electronic address: veerle.baekelandt@med.kuleuven.be.
authors.forename: Veerle
authors.initials: V
authors.lastname: Baekelandt
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000235:genetics; D002478:Cells, Cultured; D018450:Disease Progression; D015536:Down-Regulation; D015870:Gene Expression; D006801:Humans; D018345:Mice, Knockout; D009154:Mutation; D019636:Neurodegenerative Diseases / Q000235:genetics* / Q000473:pathology; D009474:Neurons / Q000473:pathology; D010300:Parkinson Disease / Q000235:genetics* / Q000473:pathology; D010766:Phosphorylation; D066329:Protein Aggregates; D066263:Protein Aggregation, Pathological / Q000235:genetics* / Q000473:pathology; D011494:Protein Kinases / Q000172:deficiency / Q000235:genetics*; D013378:Substantia Nigra / Q000378:metabolism; D051844:alpha-Synuclein / Q000378:metabolism*; D000099202:PTEN-Induced Putative Kinase
chemical_list: D066329:Protein Aggregates; D011494:Protein Kinases; D051844:alpha-Synuclein; D000099202:PTEN-Induced Putative Kinase
keywords: AAV; Aggregation; Knockdown; Knockout; Mouse; Neurodegeneration; PINK1; Parkinson's disease; Phosphorylation; α-Synuclein