Human \u03b1-synuclein overexpression in mouse serotonin neurons triggers a depressive-like phenotype. Rescue by oligonucleotide therapy

Lluis Miquel-Rio,Leticia Campa,Valentín Cóppola-Segovia,Verónica Paz,Diana Alarcón-Arís,Francesc Artigas,Analia Bortolozzi,Esther Ruiz-Bronchal,María Torres-López,Miquel Vila,Rubén Pavia-Collado,Andrés Montefeltro,Carme Casal,Raquel Revilla

doi:10.1038/s41398-022-01842-z

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.

Highlights

Parkinson’s disease (PD) is a progressive neurological disorder characterized by the neurodegeneration of dopamine (DA) neurons in the nigrostriatal pathway and the accumulation of αsynuclein (α-Syn) protein through the brain [1–3]
Extensive accumulation of human α-Syn (h-α-Syn) to efferent brain regions we addressed the question of whether raphe α-Syn pathology could lead to axonal deficits in 5-HT projection brain regions, as previously reported using different PD-like rodent models [44, 53–58]
Anxiety and depression are the most relevant neuropsychiatric symptoms that frequently occur in PD, possibly related to serotonergic dysfunctions preceding the loss of dopaminergic neurons, as the disease progresses [24, 27, 33, 37–39]

Summary

INTRODUCTION

Parkinson’s disease (PD) is a progressive neurological disorder characterized by the neurodegeneration of dopamine (DA) neurons in the nigrostriatal pathway and the accumulation of αsynuclein (α-Syn) protein through the brain [1–3]. Mutations in the SNCA gene, which encodes the α-Syn protein, can translate into α-Syn misfolding and aggregation, and early-onset forms of PD [10–12]. Increasing lines of evidence support a specific causal role of serotonergic (5-HT) dysfunction in the pathogenesis of several PD symptoms, such as tremor and dyskinesia, and anxiety, depression, anhedonia, cognitive decline, and hallucinations at early stages of the disease [21–27]. Supporting a role for α-Syn in neuropsychiatric symptoms, neuropathological studies have shown the involvement of 5-HT neurons associated with the presence of LB pathology in the raphe nuclei in idiopathic PD, as well as in patients with triplication or mutation of SNCA

Miquel-Rio et al

RESULTS

Miquel-Rio et al 3

DISCUSSION