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Human α-synuclein overexpression in mouse serotonin neurons triggers a depressive-like phenotype. Rescue by oligonucleotide therapy
dc.creator | Miquel-Rio, Lluis | es |
dc.creator | Alarcón-Arís, Diana | es |
dc.creator | Torres López, María | es |
dc.creator | Cóppola-Segovia, Valentín | es |
dc.creator | Pavia-Collado, Rubén | es |
dc.creator | Paz, Verónica | es |
dc.creator | Raquel; Bortolozzi, Analia | es |
dc.date.accessioned | 2022-12-05T19:03:46Z | |
dc.date.available | 2022-12-05T19:03:46Z | |
dc.date.issued | 2022 | |
dc.identifier.issn | 2158-3188 | es |
dc.identifier.uri | https://hdl.handle.net/11441/140187 | |
dc.description.abstract | Anxiety and depression affect 35–50% of patients with Parkinson’s disease (PD), often precede the onset of motor symptoms, and have a negative impact on their quality of life. Dysfunction of the serotonergic (5-HT) system, which regulates mood and emotional pathways, occurs during the premotor phase of PD and contributes to a variety of non-motor symptoms. Furthermore, α-synuclein (α-Syn) aggregates were identified in raphe nuclei in the early stages of the disease. However, there are very few animal models of PD-related neuropsychiatric disorders. Here, we develop a new mouse model of α-synucleinopathy in the 5-HT system that mimics prominent histopathological and neuropsychiatric features of human PD. We showed that adeno-associated virus (AAV5)-induced overexpression of wild-type human α-Syn (h-α-Syn) in raphe 5-HT neurons triggers progressive accumulation, phosphorylation, and aggregation of h-α-Syn protein in the 5-HT system. Specifically, AAV5-injected mice displayed axonal impairment in the output brain regions of raphe neurons, and deficits in brain-derived neurotrophic factor (BDNF) expression and 5-HT neurotransmission, resulting in a depressive-like phenotype. Intracerebroventricular treatment with an indatraline-conjugated antisense oligonucleotide (IND-ASO) for four weeks induced an effective and safe reduction of h-α-Syn synthesis in 5-HT neurons and its accumulation in the forebrain, alleviating early deficits of 5-HT function and improving the behavioural phenotype. Altogether, our findings show that α-synucleinopathy in 5-HT neurons negatively affects brain circuits that control mood and emotions, resembling the expression of neuropsychiatric symptoms occurring at the onset of PD. Early preservation of 5-HT function by reducing α-Syn synthesis/accumulation may alleviate PD-related depressive symptoms. | es |
dc.format | application/pdf | es |
dc.format.extent | 12p. | es |
dc.language.iso | eng | es |
dc.publisher | Springer Nature | es |
dc.rights | Atribución 4.0 Internacional | * |
dc.rights.uri | http://creativecommons.org/licenses/by/4.0/ | * |
dc.subject | Human α-synuclein | es |
dc.subject | Overexpression | es |
dc.subject | Depressive-like phenotype | es |
dc.subject | Mouse serotonin | es |
dc.subject | Oligonucleotide therapy | es |
dc.title | Human α-synuclein overexpression in mouse serotonin neurons triggers a depressive-like phenotype. Rescue by oligonucleotide therapy | es |
dc.title.alternative | Human alpha-synuclein overexpression in mouse serotonin neurons triggers a depressive-like phenotype. Rescue by oligonucleotide therapy | es |
dc.type | info:eu-repo/semantics/article | es |
dcterms.identifier | https://ror.org/03yxnpp24 | |
dc.type.version | info:eu-repo/semantics/publishedVersion | es |
dc.rights.accessRights | info:eu-repo/semantics/openAccess | es |
dc.contributor.affiliation | Universidad de Sevilla. Departamento de Fisiología Médica y Biofísica | es |
dc.relation.publisherversion | http://doi.org/10.1038/s41398-022-01842-z | es |
dc.identifier.doi | 10.1038/s41398-022-01842-z | es |
dc.journaltitle | Translational Psychiatry | es |
dc.publication.volumen | 12 | es |
dc.publication.issue | 1 | es |
dc.publication.initialPage | 79 | es |