title: Proaggregant nuclear factor(s) trigger rapid formation of α-synuclein aggregates in apoptotic neurons.
abstract: Cell-to-cell transmission of α-synuclein (αS) aggregates has been proposed to be responsible for progressive αS pathology in Parkinson disease (PD) and related disorders, including dementia with Lewy bodies. In support of this concept, a growing body of in vitro and in vivo experimental evidence shows that exogenously introduced αS aggregates can spread into surrounding cells and trigger PD-like pathology. It remains to be determined what factor(s) lead to initiation of αS aggregation that is capable of seeding subsequent propagation. In this study we demonstrate that filamentous αS aggregates form in neurons in response to apoptosis induced by staurosporine or other toxins-6-hydroxy-dopamine and 1-methyl-4-phenylpyridinium (MPP+). Interaction between αS and proaggregant nuclear factor(s) is associated with disruption of nuclear envelope integrity. Knocking down a key nuclear envelop constituent protein, lamin B1, enhances αS aggregation. Moreover, in vitro and in vivo experimental models demonstrate that aggregates released upon cell breakdown can be taken up by surrounding cells. Accordingly, we suggest that at least some αS aggregation might be related to neuronal apoptosis or loss of nuclear membrane integrity, exposing cytosolic α-synuclein to proaggregant nuclear factors. These findings provide new clues to the pathogenesis of PD and related disorders that can lead to novel treatments of these disorders. Specifically, finding ways to limit the effects of apoptosis on αS aggregation, deposition, local uptake and subsequent propagation might significantly impact progression of disease.
authors.affiliation: Neuropathology Laboratory, Department of Neuroscience, Mayo Clinic, 4500 San Pablo Road, Jacksonville, FL, 32224, USA.
authors.forename: Peizhou
authors.initials: P
authors.lastname: Jiang
authors.affiliation: Neuropathology Laboratory, Department of Neuroscience, Mayo Clinic, 4500 San Pablo Road, Jacksonville, FL, 32224, USA.
authors.forename: Ming
authors.initials: M
authors.lastname: Gan
authors.affiliation: Neuropathology Laboratory, Department of Neuroscience, Mayo Clinic, 4500 San Pablo Road, Jacksonville, FL, 32224, USA.
authors.forename: Shu-Hui
authors.initials: SH
authors.lastname: Yen
authors.affiliation: Neuropathology Laboratory, Department of Neuroscience, Mayo Clinic, 4500 San Pablo Road, Jacksonville, FL, 32224, USA.
authors.forename: Simon
authors.initials: S
authors.lastname: Moussaud
authors.affiliation: Neuropathology Laboratory, Department of Neuroscience, Mayo Clinic, 4500 San Pablo Road, Jacksonville, FL, 32224, USA.
authors.forename: Pamela J
authors.initials: PJ
authors.lastname: McLean
authors.affiliation: Neuropathology Laboratory, Department of Neuroscience, Mayo Clinic, 4500 San Pablo Road, Jacksonville, FL, 32224, USA. dickson.dennis@mayo.edu.
authors.forename: Dennis W
authors.identifier: 0000-0001-7189-7917
authors.initials: DW
authors.lastname: Dickson
mesh_terms: D015655:1-Methyl-4-phenylpyridinium / Q000633:toxicity; D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D001921:Brain / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D003600:Cytosol / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D004195:Disease Models, Animal; D006801:Humans; D034921:Lamin Type B / Q000378:metabolism*; D008810:Mice, Inbred C57BL; D009474:Neurons / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D009685:Nuclear Envelope / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D016627:Oxidopamine / Q000633:toxicity; D010766:Phosphorylation / Q000187:drug effects / Q000502:physiology; D066263:Protein Aggregation, Pathological / Q000378:metabolism* / Q000473:pathology; D019311:Staurosporine / Q000633:toxicity
chemical_list: D034921:Lamin Type B; D016627:Oxidopamine; D019311:Staurosporine; D015655:1-Methyl-4-phenylpyridinium
keywords: 6OHDA; Aggregation; Apoptosis; Lamin B1; MPP+; Nuclear membrane integrity; Parkinson’s disease; Proaggregant nuclear factors; α-Synuclein
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