ArticleTranslational psychiatry2022
Human α-synuclein overexpression in mouse serotonin neurons triggers a depressive-like phenotype. Rescue by oligonucleotide therapy.
Article in Translational psychiatry, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 32 papers.
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Who cites it
32 citing papers in PubMed, 49 citations in OpenAlex.
- A serotonergic perspective on depression in Parkinson's disease: From synaptic disruption to network failure.Neural regeneration research · 2026Article
- Increased Expression of α-Synuclein Impairs Trafficking of the Essential SNARE Protein Synaptobrevin-2.Journal of neurochemistry · 2026Article
- Involvement of Raphe Nuclei in Depressive-like Behaviors and Short-Term Memory in an Animal Model of Parkinson's Disease.ACS chemical neuroscience · 2026Article
- Locus coeruleus α-synuclein overexpression induces prodromal Parkinsonian features in mice.NPJ Parkinson's disease · 2026Article
- Comorbidity Between Mood Disorders and Chronic Somatic Diseases, With a Focus on Cardiometabolic Disease, and Its Mechanistic Crosstalk.Depression and anxiety · 2026Review
- Multiple system atrophy: advances in pathogenesis and emerging therapeutic strategies.Journal of neurology · 2025Review
- α-synuclein in Parkinson's disease: a central point of convergence with depression.NPJ Parkinson's disease · 2025Review
- A molecular convergence in the triad of parkinson's disease, depressive disorder and gut health is revealed by the inflammation-miRNA axis.Journal of neuroinflammation · 2025Article
- Depression in older adults with epilepsy: Pathophysiology and management considerations.Epilepsy & behavior : E&B · 2025Review
- Early synaptic changes and reduced brain connectivity in PD-like mice with depressive phenotype.NPJ Parkinson's disease · 2025Article
- Increase of α-Synuclein in the Peripheral Blood of Subjects with Methamphetamine Use Disorder.Psychiatry investigation · 2025Article
- The Role of Livestock Antibiotic Use in Microbiota Dysbiosis and Neuroinflammation.Antibiotics (Basel, Switzerland) · 2025Review
- Alpha-synuclein Fibrils Inhibit Activation of the BDNF/ERK Signaling Loop in the mPFC to Induce Parkinson's Disease-like Alterations with Depression.Neuroscience bulletin · 2025Article
- Revolution of AAV in Drug Discovery: From Delivery System to Clinical Application.Journal of medical virology · 2025Review
- Chronic stress induces depression-like behaviors and Parkinsonism via upregulating α-synuclein.NPJ Parkinson's disease · 2025Article
- Modelling human neuronal catecholaminergic pigmentation in rodents recapitulates age-related neurodegenerative deficits.Nature communications · 2024Article
- Review
- Review
- The 'α-synucleinopathy syndicate': multiple system atrophy and Parkinson's disease.Journal of neural transmission (Vienna, Austria : 1996) · 2024Review
- Recent Advances in Clinical Trials in Multiple System Atrophy.Current neurology and neuroscience reports · 2024Review
Corrections and comments
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Authors and funding
14 authors at 5 institutions in 3 countries.
Funding
No grant is acknowledged in the PubMed record.
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.
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