In a groundbreaking exploration of neurodegenerative and psychiatric intersections, recent research has illuminated the pivotal role of α-synuclein (α-syn) as a molecular nexus in Parkinson’s disease (PD) and depression. Often considered distinct entities, PD and depression are now emerging as intimately linked through converging pathogenic pathways, with α-synuclein accumulation serving as a central orchestrator of their intertwined progression.
Serotonin, a critical neurotransmitter deeply involved in mood regulation, cognition, and circadian rhythms, is substantially implicated in non-motor symptoms of PD. The brainstem’s raphe nuclei (RN) house serotonergic neurons that project widely to cortical and subcortical brain regions. The pathological accumulation of α-syn in these nuclei during early Braak stages signifies a prelude to early non-motor manifestations of PD, such as depression, occurring well before the onset of classical motor symptoms linked to dopaminergic neuronal loss. Imaging and postmortem analyses corroborate the selective vulnerability and substantial loss of serotonin transporter binding and serotonergic neurons in PD, underscoring a mechanistic basis for prodromal depressive symptoms stemming from direct α-syn-induced serotonergic dysfunction.
Experimental animal models have provided mechanistic insights, revealing that overexpression of human wild-type α-syn in serotonergic neurons leads to aggregation, impaired brain-derived neurotrophic factor (BDNF) production, disrupted serotonin neurotransmission, and related depressive-like behaviors. Remarkably, targeted suppression of α-syn synthesis in these cells reverses these deficits, highlighting α-syn as a modifiable factor in the neuropsychiatric dimension of PD. This points to a model in which α-syn pathology is not merely a downstream consequence but an active driver of depression through serotonergic circuit impairment.
Dopaminergic transmission disturbances remain a hallmark of PD pathophysiology, further entangling the relationship between PD and depression. Beyond the loss of substantia nigra dopamine neurons, reductions in dopamine transporter (DAT) availability have been observed in depressed individuals, although receptor availability differences remain inconclusive. Stress-induced hypercortisolemia exacerbates α-syn aggregation and dopaminergic neuronal loss, likely mediated through toxic dopamine metabolites such as DOPAL, which foster α-synuclein misfolding and mitochondrial perturbations. These findings expose a vicious cycle wherein psychological stress and α-syn aggregation coalesce to deteriorate dopaminergic circuits, thereby driving both motor and affective symptoms.
The impact of α-syn extends into the noradrenergic domain, with norepinephrine (NE) depletion emerging early in PD brainstem pathology. Loss of locus coeruleus-derived NE, mirroring alterations in dopamine and serotonin systems, has been linked to cognitive, autonomic, and mood dysfunctions in PD. Intriguingly, α-syn modulation of NE transporter trafficking via microtubule interactions adds a layer of complexity, suggesting that aberrant α-syn can directly interfere with NE signaling. Clinically, NE reuptake inhibitors have demonstrated efficacy in ameliorating depressive symptoms in PD without improving motor deficits, indicating neurotransmitter-specific therapeutic avenues.
Neuroinflammation serves as a convergent mechanism exacerbating both PD and depression pathology. Chronic stress and hypothalamic-pituitary-adrenal (HPA) axis dysfunction reduce glucocorticoid receptor (GR) efficacy, undermining microglial and astrocytic control over inflammatory responses. This loss catalyzes relentless production of pro-inflammatory cytokines and glial activation. Crucially, studies show that restoring GR signaling mitigates α-syn accumulation and dopaminergic neuron loss by modulating key inflammatory pathways such as NFκB and TLR9. Additionally, α-syn’s pathological interaction with microglial purinergic receptors like P2X7 amplifies mitochondrial dysfunction and neuroinflammation. These findings suggest that neuroinflammatory escalation driven by α-syn and stress-induced GR dysregulation fuels a destructive feedback loop worsening PD outcomes.
Altered synaptic plasticity also emerges as a critical interface between stress, α-syn, and PD progression. Psychosocial stress influences dopaminergic receptor availability and synaptic proteins in PD models, suggesting vulnerability of plasticity-related mechanisms to chronic corticosterone exposure. Concurrently, α-syn exhibits a dual role in modulating dopamine release, inducing activity-dependent facilitation followed by suppression, contributing to synaptic dysregulation. Although the detailed molecular crosstalk involving glucocorticoids, GRs, and α-syn in synaptic plasticity remains to be elucidated, these dynamics likely potentiate the emergence of affective symptoms and accelerate neural circuit degenerations.
Mitochondrial dysfunction, a converging hallmark of neurodegenerative and mood disorders, profoundly intersects with α-syn pathology. Synergistic toxicity induced by concurrent corticosterone and neurotoxic insults exacerbates oxidative stress, depletes antioxidant defenses, and impairs mitochondrial respiration, particularly within the substantia nigra. Furthermore, α-syn aggregation driven by reactive oxygen species fosters a pernicious cycle of mitochondrial membrane disruption and energy failure. Despite gaps in understanding the modulation of these processes by glucocorticoid signaling, the intimate link between mitochondrial impairment and α-syn propagation constitutes a key pathological axis in PD-depression comorbidity.
Apoptotic pathways influenced by α-syn and diminished neurogenesis further erode neuronal integrity. The hippocampus, a rare site of adult neurogenesis, relies heavily on BDNF signaling for neuronal survival, plasticity, and differentiation. Genetic variants reducing BDNF expression substantially elevate depression risk in PD and correlate with motor symptom severity. α-Syn overexpression disrupts BDNF production, serotonergic innervation, and key synaptic proteins within hippocampal circuits, precipitating depressive phenotypes that precede motor decline. Pharmacological modulation restoring BDNF levels demonstrates symptomatic improvement, underscoring the centrality of trophic support loss in PD-associated depression.
Emerging evidence implicates serum and glucocorticoid-regulated kinase 1 (SGK1) as a modulator of apoptosis and α-syn accumulation, though conflicting patterns of its expression in depression and PD models temper conclusive interpretations. Similarly, other apoptosis-related mediators with glucocorticoid receptor elements, such as BCL2, warrant deeper investigation within PD-depression frameworks. Mitochondrial-related apoptotic signaling compounds this vulnerability, highlighting multiple overlapping mechanisms driving neuronal loss.
At a genomic level, integrated analyses of GWAS data reveal shared genetic loci linking PD patients with SNCA polymorphisms and individuals with major depressive disorder. Notable shared genes include DYRK1A, known for phosphorylating α-syn and promoting dopaminergic and serotonergic neuronal death, and HLA-DRB1 and HLA-DQA1, which facilitate α-syn presentation to immune cells, fostering inflammation. The vitamin D receptor pathway materializes as a significant genetic susceptibility axis, presenting potential targets for therapeutic intervention aimed at mitigating exacerbated pathology when depression and PD coexist.
Complementing this genetic overlap, transcriptomic meta-analyses identify a set of differentially expressed genes equally perturbed in PD and depression, predominantly involved in innate immune activation and intrinsic apoptotic signaling. Although expression changes are modest, these reflect sustained low-grade inflammation and neurodegenerative processes, possibly potentiated by α-syn dysregulation in vulnerable brain regions.
Collectively, these multi-faceted data converge on the conceptualization of α-synuclein as a critical molecular bridge between Parkinson’s disease and depression. The bidirectional pathology, encompassing neurotransmitter disruptions, neuroinflammation, synaptic dysfunction, mitochondrial impairment, and impaired neurogenesis, underscores the complexity of the PD-depression interface. Targeting α-syn and its interconnected pathways offers a promising paradigm for earlier diagnosis, refined stratification, and novel therapeutic strategies that address both motor and affective symptoms, potentially altering the course of this debilitating dual affliction.
This integrative perspective not only reshapes our understanding of Parkinson’s disease beyond its motor phenotype but also elevates depression from a mere comorbidity to an intrinsic component of PD pathology. Future research harnessing longitudinal, mechanistic, and interventional approaches is imperative to unravel the intricacies of α-syn’s role, transforming patient care through precision medicine tailored to this devastating neuropsychiatric synergy.
Subject of Research:
Investigating the molecular and genetic interplay of α-synuclein in Parkinson’s disease and depression, with a focus on shared pathogenic mechanisms.
Article Title:
α-synuclein in Parkinson’s disease: a central point of convergence with depression.
Article References:
Yusuf, A.M., Ilce, B.Y., Alhaj, H.A. et al. α-synuclein in Parkinson’s disease: a central point of convergence with depression. npj Parkinsons Dis. 11, 329 (2025). https://doi.org/10.1038/s41531-025-01167-w
Image Credits:
AI Generated
