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

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.

On the heterogeneity of depression in Parkinson’s disease

Depression in Parkinson’s disease (PD) is one of the leading manifestations of the disease, which reduces quality of life in patients.Objective: to compare the clinical features of depression at different stages of PD.Patients and methods. Examinations were made in 162 PD patients aged 62.14±1.99 years without dementia (PD duration, 5.78±0.58 years; Stage, 2.5±0.6). The Unified PD Rating Scale (UPDRS), the Beck Depression Inventory (BDI), and the Spielberger Inventory, the 16-Item PD Fatigue Scale (PFS-16), and the Starkstein Apathy Scale were examined. Dopaminergic agents (DAAs) were prescribed when movement disorders were insufficiently corrected. Antidepressants were not used during the investigation. The follow-up period was 18 months.Results and discussion. Depression was detected in 136 (84%) patients. Depression symptoms appeared in 16 (12%) patients within 1–8 years before the onset of motor symptoms (MS), in 37 (27%) in the first 2 years after the onset of MS, in 44 (32%) at Hoehn–Yahr stages 2–3 without motor fluctuations (MFs), and in 39 (29%) at the onset of MF. The most severity of depression was noted in cases of its development at the premotor stage and in the period of MF occurrence. During the follow-up, the manifestations of depression disappeared in 16% of the patients taking a DAA; these were relapsing-remitting in 9%, progressive in 11%, or remained stable in 64%. The patients with depression occurring at the premotor stage had a progressive course of depression and a low DAA efficacy: an increase in severity in 30% of cases despite therapy and a reversal in only 10% of cases (versus 25–45% of those at depression onset in the presence of MS). In cases of depression occurring in the first 2 years after MS onset, its reversal was observed in 45%; the group of patients with depression onset in the presence of MF showed a stable course with slight severity fluctuations in 77.8%.Conclusion. Depression in PD is a heterogeneous affective disorder. There is a relatively favorable course of depression when the latter occurs in the first two years of MS onset. Along with DAA inefficacy, the more severity of depression is noted when the latter occurs in the premotor phase of PD and at the stage of MF.

Occurrence of internal diseases in the premotor phase of Parkinson’s disease by analyzing a large database covering a whole population

The premotor phase of Parkinson’s disease (PD) precedes the appearance of motor symptoms by years. Many non-motor diseases have been associated with an increased risk of developing PD, but results of these studies are conflicting. The aim of this study was to investigate the occurrence of certain internal diseases (metabolic, circulatory, gastrointestinal) based on diagnosis codes, before the diagnosis of PD. There were 5209 patients included in the study who received diagnosis of PD at least in 2 years and we analyzed data retrospectively between 2004 and 2016. Out of metabolic diseases dyslipidemia (41%) and diabetes mellitus (32%), out of circulatory diseases hypertension (89%) and ischemic heart disease (51%) and out of gastrointestinal diseases gastroesophageal reflux disease (51%) and gallstones (25%) were the first two most common disorders in the examined PD patients. This is the first study in Hungary which analyzed PD in a large database in the context of internal diseases, and raised the possibility of a link between dyslipidemias, diabetes mellitus, hypertension, ischemic heart disease, gastooesophagial reflux, gallstones and PD.

Erectile Dysfunction Preceding Clinically Diagnosed α-Synucleinopathies: A Case-Control Study in Olmsted County

Objective. Autonomic symptoms are common in α-synuclein disorders: multiple system atrophy (MSA), Parkinson’s disease (PD), dementia with Lewy bodies (DLB), and Parkinson’s disease with dementia (PDD). These symptoms may precede the motor findings/clinical diagnosis by years. Erectile dysfunction (ED) is an autonomic symptom that has rarely been studied in these α-synuclein disorders. In this population-based, case-control study, we investigated the association between premonitory erectile dysfunction surfacing prior to the clinical-motor manifestations of these α-synucleinopathies. Methods. We used the medical record-linkage system of the Rochester Epidemiology Project to identify cases of α-synucleinopathies in Olmsted County from 1991 to 2010. Each male case was matched by age (±1 year) of symptom onset and sex to a control. We reviewed complete medical records of cases and controls to detect erectile dysfunction prior to the clinical-motor onset of α-synucleinopathies of any type. We used conditional logistic regression to calculate the odds ratio of all α-synucleinopathies, as well as by type, adjusting for diabetes, coffee, and smoking. Results. A history of male erectile dysfunction was associated with 1.5-fold increased odds of an α-synucleinopathy diagnosis of any type in univariate analyses (p=0.06). When stratifying α-synucleinopathies by type, early erectile dysfunction was most frequent in MSA cases than matched controls (45% vs. 9%). Premotor phase ED was next most frequent among the DLB cases (46% vs. 27% among the controls; OR = 2.83, p=0.03; when adjusted for diabetes, smoking, and coffee, OR = 2.98, p=0.04). Premotor phase ED was not significantly associated with PD or PDD. Conclusions. Early erectile dysfunction may be a premotor symptom of MSA and DLB, reflecting premonitory dysautonomia. It was not associated with premotor PD or PDD.