Aug 2026· Frontiers in Aging Neuroscience· Vol 18· 0 citations· 35 references
TL;DR
The biomarker and therapeutic potential of STX1A remains preliminary because diagnostic performance, disease specificity, longitudinal stability, and causal relevance have not been adequately validated and future studies using cell-type-specific STX1A manipulation, rescue experiments, electrophysiology, and multicenter longitudinal cohorts are required to define the biological and clinical significance of STX1A in PD.
Abstract
Parkinson’s disease (PD) is a progressive neurodegenerative disorder characterized by degeneration of substantia nigra dopaminergic neurons, α-synuclein pathology, and widespread synaptic dysfunction. Syntaxin-1A (STX1A), a presynaptic Qa-SNARE protein, is essential for synaptic vesicle fusion and also interacts with proteins involved in ion-channel regulation and neuronal excitability. Several animal, extracellular-vesicle, and peripheral-blood studies have reported reduced STX1A abundance in PD. However, the available evidence is predominantly cross-sectional and does not establish whether STX1A downregulation is a cause of PD pathology, a consequence of neuronal and synaptic loss, or a peripheral correlate of disease. This narrative review critically evaluates evidence linking STX1A to PD and distinguishes experimentally supported observations from mechanistic hypotheses. Potential relationships with calcium dysregulation, mitochondrial injury, ferroptosis, and neuroimmune signaling are discussed as testable models rather than established pathways. Direct evidence connecting STX1A to the gut–brain axis in PD is currently lacking and is therefore considered primarily as a future research direction. The biomarker and therapeutic potential of STX1A remains preliminary because diagnostic performance, disease specificity, longitudinal stability, and causal relevance have not been adequately validated. Future studies using cell-type-specific STX1A manipulation, rescue experiments, electrophysiology, and multicenter longitudinal cohorts are required to define the biological and clinical significance of STX1A in PD.
Parkinson’s disease (PD) is an insidious neurodegenerative disease that is marked by loss of dopaminergic cells of the substantia nigra (SN) and aggregation of misfolded a-synuclein proteins. It is characterized by typical motor symptoms such as tremor, rigidity, bradykinesia, and postural instability, along with a wide range of non-motor manifestations including cognitive impairment, autonomic dysfunction, sleep disturbances, and mood disorders.The pathophysiology of PD is multifactorial, as it entails protein aggregation, mitochondrial dysfunction, oxidative stress, neuroinflammation, and genetics. Although significant advancements have been made in levodopa-based therapies and surgical interventions such as deep brain stimulation, these approaches primarily provide symptomatic relief and do not prevent disease progression. Emerging therapeutic strategies, including gene therapy, RNA-based therapeutics, immunotherapy, and stem cell interventions, are currently under investigation for their potential disease-modifying effects. Furthermore, patient-centered and precision medicine approaches are becoming increasingly important in PD management. This review integrates clinical, molecular, and therapeutic perspectives, with particular emphasis on challenges associated with bench-to-bedside translation. It also highlights the urgent need for reliable biomarkers, early diagnosis, and multidisciplinary disease-modifying strategies for future therapeutic interventions.
Jeewanjot Singh, Subhi Sharma, Prabhjot Singh et al.· Advances in Modern Biomedici...· 0 citations
Parkinson’s disease (PD) is a progressive neurodegenerative disorder characterized by dopaminergic neuronal loss, neuroinflammation, oxidative stress, mitochondrial dysfunction, and α-synuclein accumulation. Current treatments mainly provide symptomatic relief and do not substantially alter disease progression, highlighting the need for effective disease-modifying therapies. Semaglutide, a glucagon-like peptide-1 (GLP-1) receptor agonist, has emerged as a potential neuroprotective agent. This narrative review evaluates the therapeutic potential of semaglutide in PD, focusing on its molecular mechanisms and preclinical and emerging clinical evidence. Experimental studies suggest that semaglutide crosses the blood-brain barrier and activates GLP-1 receptors in neuronal and glial cells, reducing microglial activation, neuroinflammation, and oxidative stress while improving mitochondrial function, cellular metabolism, and neuronal survival. It may also reduce α-synuclein aggregation and improve motor and cognitive outcomes in experimental models. Although findings are promising, clinical evidence remains limited. Well-designed randomized trials are needed to establish its efficacy, safety, optimal dosing, and disease-modifying potential in PD.
Dipesh Kumar, Renuka Sahu, Naveen Kumar et al.· International Journal of Sci...· 0 citations
Parkinson’s disease (PD) is characterized by degeneration of dopaminergic neurons in the substantia nigra pars compacta, but the molecular events preceding neuronal loss remain unclear. Here, we combine spatial transcriptomics, spatial proteomics, and α-synuclein (αSyn) seed amplification assays to profile post-mortem midbrain tissue from controls, incidental Lewy body disease (iLBD), PD, Alzheimer’s disease (AD), and AD with Lewy body pathology (AD + LBP). We find that αSyn seeding activity correlates with dopaminergic neuron loss in PD-spectrum cases but not in AD-associated LBP, indicating disease-context dependent relationships between αSyn pathology and neurodegeneration. In iLBD, before overt substantia nigra Lewy pathology or detectable αSyn aggregation, we detect increased expression of the complement component C1QC together with loss of inhibitory synaptic markers. These findings support early complement-associated remodeling of inhibitory synapses as a potential pathogenic event preceding overt αSyn aggregation and neuronal degeneration in PD. Parkinson’s disease is associated with dopaminergic neuron loss, but the molecular events preceding degeneration remain unclear. Here, the authors show that early complement associated pruning of inhibitory synapses precedes overt α-synuclein aggregation and neuronal loss in prodromal synucleinopathy.
Svenja-Lotta Rumpf, Felix L. Struebing, Karsten Nalbach et al.· Nature Communications· 0 citations
Background: Parkinson’s disease (PD) exhibits remarkable clinical heterogeneity, with substantial variability in motor progression, cognitive decline, and the development of non-motor manifestations. Although the propagation of pathological alpha-synuclein is considered a central mechanism of PD pathogenesis, it does not fully explain why specific neuronal populations demonstrate differential susceptibility to degeneration. Emerging evidence suggests that selective neuronal vulnerability is determined by the interaction of multiple biological domains, including calcium homeostasis, mitochondrial bioenergetic capacity, lysosomal function, axonal architecture, synaptic resilience, and neuroinflammatory responses. Methods: A structured critical narrative review was performed using PubMed/MEDLINE, Scopus, and Web of Science databases from inception to March 2025. Only full-text articles published in English and peer-reviewed journals were included. Evidence from human post-mortem studies, genetic analyses, biomarker investigations, experimental models, induced pluripotent stem cell studies, and longitudinal clinical cohorts were systematically synthesised to identify the principal mechanisms underlying selective neuronal vulnerability and their potential translational application. To capture evidence published after this electronic cut-off, a supplementary manual review of reference lists of key systematic reviews and landmark publications was conducted up to the date of manuscript submission; references with 2025 or 2026 publication dates entered through this supplementary process. The supplementary manual review was conducted as a targeted scan of reference lists of key systematic reviews and high-impact publications identified during the primary search and did not constitute an independent updated systematic search. Results: Five interconnected biological domains emerged as key determinants of neuronal susceptibility in PD: calcium-mediated metabolic stress associated with autonomous pacemaker activity, mitochondrial dysfunction and energetic failure, impaired lysosomal degradation and proteostasis (particularly involving the GBA1–glucocerebrosidase pathway), vulnerability related to extensive axonal and synaptic architecture, and neuroinflammatory mechanisms involving microglial and astrocytic activation. Among these domains, the lysosomal pathway currently provides the strongest translational link between molecular mechanisms and measurable clinical outcomes. Based on this integrated framework, we propose the Parkinson’s Vulnerability Index (PVI), a hypothesis-generating multidimensional model combining genetic, enzymatic, alpha-synuclein seeding, cognitive, olfactory, and neuroimaging biomarkers to facilitate biological stratification and improve the design of mechanism-targeted clinical trials. Conclusions: Selective neuronal vulnerability provides a complementary framework to alpha-synuclein propagation models for understanding the heterogeneity of PD. The proposed PVI is not intended as a diagnostic or prognostic clinical instrument but as a research tool requiring prospective validation. Future precision medicine approaches in PD may benefit from integrating vulnerability-related biomarkers with existing biological staging systems to identify patients most likely to benefit from targeted disease-modifying therapies.
Livia Livinț-Popa, Andreea Nicolaie, A. Maștaleru et al.· Medical Science· 0 citations
Parkinson’s disease (PD) is traditionally described as a dopaminergic neurodegenerative disorder driven by α-synuclein aggregation and selective neuronal loss in the substantia nigra pars compacta. While this characterization captures the core clinical and pathological features, it does not fully explain disease initiation and progression. Converging evidence from human genetics, cellular and structural biology, and systems neuroscience now supports a unified framework in which PD results from the progressive erosion of mitochondrial resilience. Here, mitochondrial resilience denotes the capacity of neuronal mitochondrial networks to withstand stress and recover bioenergetic and cellular homeostasis through coordinated quality control, metabolic adaptation, and organelle communication. Rare, high-impact monogenic mutations in
PINK1
,
PRKN
(encoding Parkin), PARK7 (
DJ-1)
,
LRRK2
, and
SNCA
, along with common risk variants identified in genome-wide association studies, converge on interconnected pathways that govern mitochondrial quality control, bioenergetics, organelle dynamics, and cellular stress responses. These vulnerabilities are most pronounced in the highly energetic dopaminergic neurons of the substantia nigra, where sustained calcium cycling, high bioenergetic demand, and environmental stressors increase cellular susceptibility. Research has moved beyond early observations of respiratory chain impairment and oxidative stress to reveal context-specific disruptions in PINK1/Parkin-mediated mitophagy, lysosomal trafficking, mitochondrial-derived vesicle dynamics, and neuroimmune signaling. This integrated framework reframes PD as a disorder of impaired cellular maintenance rather than solely a consequence of late-stage degenerative processes. It provides a translational shift from mechanism-based biomarkers to early detection of mitochondrial failure and supports therapeutic strategies aimed at restoring mitochondrial function and resilience, offering a direct route to disease-modifying neuroprotection in PD and potentially other neurodegenerative disorders.
Oscar Arias-Carrión, Magdalena Guerra-Crespo, L. O. Soto-Rojas et al.· Frontiers in Pharmacology· 0 citations
Overall, this review makes a case for integrative, pathway-based therapeutic models, and multiple approaches may facilitate for drug development, biomarker identification and patient management in Alzheimer's disease.