Muhammad Zain

Background: Parkinson’s disease (PD) is the second most common neurodegenerative condition in the world and is defined by the continuous degeneration of dopaminergic neurons in the substantia nigra pars compacta, accompanied by intracellular deposition of α-synuclein (α-syn) in Lewy bodies.¹ Depression in PD (DPD) is the most frequent neuropsychiatric comorbidity in patients with PD, occurring in around 40% of cases, and is the single strongest predictor of reduced quality of life.¹˒² Importantly, symptoms of depression often appear years before the onset of motor impairment, which indicates that DPD also has a neurodegenerative etiology.¹˒² Currently, knowledge on molecular processes involved in the link between α-syn pathology and depression is incomplete, and there is no medication that addresses this biological relationship.¹˒²˒³

Objective: The purpose of this narrative review is to examine the theory that the accumulation of α-syn within serotonergic cells in the dorsal raphe nucleus is the main mechanism causing DPD, which is mutually reinforced through chronic psychological stress.

Search Methods: A search for relevant literature using PubMed was carried out from  2018 and 2025. The key search terms used included “Parkinson’s disease depression,” “alpha-synuclein serotonin,” “dorsal raphe nucleus neurodegeneration,” “BDNF serotonergic dysfunction,” and “chronic stress alpha-synuclein.”

Results: Miquel-Rio et al. (2022) demonstrated that the selective overexpression of α-synuclein in mouse serotonin neurons of the raphe nucleus led to progressive accumulation of phosphorylated α-synuclein, loss of axonal density of the serotonin transporter, decreased 5-HT release in the medial prefrontal cortex, and loss of BDNF in the hippocampus. These occurred before neuronal body loss, showing an axonal therapeutic window prior to neuron death.⁴ The mice also displayed depression-like behavior without any signs of dopaminergic pathology, thereby validating the role of serotonergic α-synuclein pathology.⁴ The study conducted by Xia et al. (2025) further established that chronic unpredictable mild stress (CUMS)  caused a significant increase in α-synuclein protein levels, whereas deletion of the Snca gene completely protected them from depression.⁵ In addition, α-syn phosphorylation was found in aged wild-type mice exposed to early life stress, indicating that chronic stress may be able to induce the development of PD pathology.⁵ In a 2025 follow-up work conducted by Miquel-Rio et al., extensive loss of synapses in prefrontal and hippocampal networks prior to neurodegeneration was discovered, with postmortem human PD tissue validating these findings. Resting-state fMRI on 106 patients with PD indicated dose-dependent reduction in connectivity of salience network in correlation with the severity of depression.⁶˒⁷ Lastly, in the 2022 work conducted by Miquel-Rio et al., it was observed that IND-ASO (antisense oligonucleotide conjugated with indatraline) showed α-syn gene expression reduction of ~35%, along with the phosphorform reduction of ~65% leading to full recovery of 5-HT neurotransmission and alleviation of depressive behavior.⁴ Additionally, Alarcón-Arís et al. (2020) validated IND-ASO intranasal efficacy.⁸

Conclusion: Collectively, this literature establishes that α-syn accumulation in dorsal raphe serotonin neurons is a mechanistically sufficient and early driver of DPD, reinforced by a bidirectional loop in which chronic stress further upregulates α-syn and accelerates PD-like pathological aggregation. Synaptic and connectivity disruptions are detectable before neurodegeneration and correlate with clinical severity, positioning salience network fMRI as a promising treatment biomarker. IND-ASO represents the first preclinical proof-of-concept for a disease-modifying therapy targeting this pathway. Future priorities include human trials of intranasal IND-ASO delivery, longitudinal fMRI studies as treatment endpoints, and evaluation of depression as a prodromal biomarker PD before motor symptoms emerge.

Works Cited:

1. Jellinger KA. The pathobiological basis of depression in Parkinson disease: challenges and outlooks. J Neural Transm (Vienna). 2022;129(12):1397-1418. doi:10.1007/s00702-022-02559-5
2. Ahmad MH, Rizvi MA, Ali M, Mondal AC. Neurobiology of depression in Parkinson’s disease: Insights into epidemiology, molecular mechanisms and treatment strategies. Ageing Res Rev. 2023;85:101840. doi:10.1016/j.arr.2022.101840
3. Wang Z, Wei H, Xin Y, Qin W. Advances in the study of depression and anxiety in Parkinson’s disease: A review. Medicine (Baltimore). 2025;104(10):e41674. doi:10.1097/MD.0000000000041674
4. Miquel-Rio L, Alarcón-Arís D, Torres-López M, et al. Human α-synuclein overexpression in mouse serotonin neurons triggers a depressive-like phenotype. Rescue by oligonucleotide therapy. Transl Psychiatry. 2022;12(1):79. doi:10.1038/s41398-022-01842-z
5. Xia D, Xiong M, Yang Y, et al. Chronic stress induces depression-like behaviors and Parkinsonism via upregulating α-synuclein. npj Parkinsons Dis. 2025;11(1):139. doi:10.1038/s41531-025-00998-x
6. Miquel-Rio L, Jericó-Escolar J, Sarriés-Serrano U, et al. Early synaptic changes and reduced brain connectivity in PD-like mice with depressive phenotype. npj Parkinsons Dis. 2025;11(1):242. doi:10.1038/s41531-025-01073-1
7. Liu Q, Mao Z, Tan C, et al. Resting-state brain network in Parkinson’s disease with different degrees of depression. Front Neurosci. 2022;16:931365. doi:10.3389/fnins.2022.931365
8. Alarcón-Arís D, Pavia-Collado R, Miquel-Rio L, et al. Anti-α-synuclein ASO delivered to monoamine neurons prevents α-synuclein accumulation in a Parkinson’s disease-like mouse model and in monkeys. EBioMedicine. 2020;59:102944. doi:10.1016/j.ebiom.2020.102944