Moretto E, Masato A, Panzi C
… +8 more, Lopes AT, Stuart S, De La-Rocque S, Caso MG, White IJ, Harris SS, Busche MA, Schiavo G
Nat Neurosci
· 2026 Jun · PMID 42243402
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Impairments in axonal transport have been implicated in the pathogenesis of tauopathies, including frontotemporal dementia and Alzheimer's disease, yet the underlying mechanisms and reversibility of these deficits are la...Impairments in axonal transport have been implicated in the pathogenesis of tauopathies, including frontotemporal dementia and Alzheimer's disease, yet the underlying mechanisms and reversibility of these deficits are largely unknown. In particular, the impacts of tau mutations, phosphorylation and aggregation on axonal transport in vivo remain controversial. By using two-photon imaging of axonal transport of BDNF granules in the mouse cortex, we reveal that deficits in axonal transport arise in vivo at early stages of tau pathology, preceding tangle formation and neuronal death. Mechanistically, these impairments are caused by the enlargement of tau envelopes on microtubules, which act as functional barriers for transport. Crucially, these deficits are reversed by inhibiting MAPK p38α. Together, our work demonstrates that tau pathology causes reversible deficits in axonal transport in vivo, posing the basis for pharmacological interventions to restore the physiological flux of axonal organelles and cargoes in tauopathies.
Trauma to the spinal cord initiates an inflammatory response that causes secondary damage, which collectively can result in loss of function below the level of the injury. The unbalanced risk-benefit-ratio of methylpredn...Trauma to the spinal cord initiates an inflammatory response that causes secondary damage, which collectively can result in loss of function below the level of the injury. The unbalanced risk-benefit-ratio of methylprednisolone led to development of therapeutic nanoparticles (NP) that associate with circulating monocytes and neutrophils to reduce inflammation and secondary damage, and improve functional recovery in a female mouse model of cervical hemisection spinal cord injury. Herein, we investigate the mechanisms occurring during the acute phase of injury by which NPs directly and indirectly modulate the phenotype and trafficking of monocytes and neutrophils, and computationally catalog the communication network among cell types within the injury microenvironment. Using adoptive transfer to monitor trafficking, NP treatment reduced the extent of myeloid cell recruitment to the injury, yet did not impact the composition of adoptively transferred monocytes or neutrophils. The proportion of inflammatory monocytes was reduced with NP treatment, and single cell sequencing analysis indicated increased polarization towards pro-regenerative phenotypes. Sequencing analysis also demonstrated that outgoing signals from monocytes and neutrophils influenced the phenotype of numerous cell types, including endothelial cells, fibroblasts, oligodendrocyte progenitor cells, and Schwann cells. Signaling between cell compartments involves a combination of soluble and matrix signals, with NP treatment enhancing expression of genes associated with anti-inflammatory phenotypes, angiogenesis, neuroprotection, and promotion of axon outgrowth or decreasing expression of inhibitors to regeneration. Collectively, NP delivery leads to direct and indirect effects on monocytes and neutrophils, which subsequently influence gene expression and intercellular signaling networks that promote a pro-regenerative environment. Spinal cord injury is a serious trauma that results in significant loss of motor function and lacks successful clinical treatment options. We have previously demonstrated that polymeric nanoparticles can attenuate inflammation to reduce the severity of secondary injury, resulting in improved functional outcomes. Here, we computationally explore the mechanisms through which these nanoparticles alter the inflammatory response and improve the regenerative trajectory of the injury.
The 5-methylcytosine (mC) RNA modification regulates multiple aspects of RNA metabolism; however, its contribution to pathological pain remains poorly understood. Here, we investigated the role of the mC reader Alyref in...The 5-methylcytosine (mC) RNA modification regulates multiple aspects of RNA metabolism; however, its contribution to pathological pain remains poorly understood. Here, we investigated the role of the mC reader Alyref in a mouse (of either sex) model of complete Freund's adjuvant (CFA)-induced chronic inflammatory pain. We observed a marked and sustained upregulation of in nociceptive neurons of the dorsal root ganglion (DRG) following CFA administration. Conditional deletion of in Na1.8 nociceptive neurons significantly exacerbated thermal and cold hypersensitivity, mechanical allodynia, and hyperalgesia. These behavioral abnormalities were accompanied by pronounced activation of microglia and astrocytes in the spinal dorsal horn, along with elevated expression of proinflammatory mediators, indicating enhanced neuroinflammation and central sensitization. Mechanistically, Alyref directly binds to mC-modified mRNA and promotes its nuclear export, thereby maintaining cytoplasmic Ccn3 expression in DRG neurons. Loss of impaired mRNA export, reduced Ccn3 expression, and was associated with an increased level of MMP-9, a key mediator of neuroinflammatory pain signaling. Collectively, these findings identify Alyref as a protective regulator in chronic inflammatory pain by restraining neuroinflammation and limiting the emergence of neuropathic pain-like features. Our study highlights a previously unrecognized role of mC-dependent RNA regulation in nociceptive sensitization and suggests Alyref as a potential therapeutic target for pathological pain.
The mammalian vestibular system has two types of sensory receptors (hair cells), type I and type II. Understanding the roles of type I and II hair cells in the vestibular system's control of motor behaviors is difficult...The mammalian vestibular system has two types of sensory receptors (hair cells), type I and type II. Understanding the roles of type I and II hair cells in the vestibular system's control of motor behaviors is difficult because most primary vestibular neurons receive inputs from both hair cell types. To test if type I hair cells are required for motor behaviors, we ablated them from peripheral zones of vestibular epithelia in young adult (3-6 months) (experimental) mice of both sexes, then examined motor behaviors and brainstem neuronal responses. Over 90% of peripheral type I hair cells were ablated from vestibular organs by one week post-tamoxifen, while central type I and all type II hair cell numbers did not change significantly out to 8 weeks post-tamoxifen. Right after ablation, mice displayed no obvious locomotor abnormalities. However, they could only balance on a rotarod or beam for a few seconds, and gains of the horizontal vestibulo-ocular reflex were reduced by 50%. Deficits persisted to 8 weeks post-tamoxifen, with one exception: 3-6 month old mice showed partial recovery of rotarod performance after 4 weeks post-tamoxifen, likely due to adaptive motor strategies. Remarkably, 16 month-old mice with type I hair cell ablation failed to recover rotarod function. Motion-induced CFOS expression in vestibular brainstem neurons was nearly eliminated after hair cell ablation, suggesting inputs from vestibular organs had changed significantly. This study demonstrates that peripheral type I hair cells are essential for a vestibular reflex and for some tasks requiring balance and motor coordination. This study demonstrates that a specific subpopulation of vestibular sensory receptor cells (peripherally located type I hair cells) is required in adult mice to maintain normal vestibular function, including the vestibulo-ocular reflex, balance and motor coordination, and neuronal responses to a motion stimulus. These findings have implications for the underlying pathology in some types of balance disorders and may inform new strategies to restore vestibular function after hair cell damage or degeneration.
Directional dendritic transport of late endosomes (LEs) retrogradely toward the soma is required for fusion with lysosomes and for degradation in the soma. Both dendritic motility of LEs and somatic degradation require R...Directional dendritic transport of late endosomes (LEs) retrogradely toward the soma is required for fusion with lysosomes and for degradation in the soma. Both dendritic motility of LEs and somatic degradation require RAB7A. Similarly, interference with dynein function reduces motility of LEs and results in degradative failure. Blocking dynein function also impairs normal dendrite growth, suggesting that motility of LEs and subsequent fusion with lysosomes might be required for dendrite growth. RAB7A and dynein are mechanistically linked via the dynein-interacting RAB7A effector RILP. RILP also binds the LE-lysosome fusion tether HOPS. In non-neuronal cells, downregulation of RILP leads to impaired degradation due to deficiencies in LE transport and fusion defects with lysosomes. In this work, we express a separation-of-function mutant of RAB7A (RAB7A-L8A) incapable of RILP binding. Based on the results in non-neuronal cells, we hypothesized that both endosome motility and degradation in neurons depended on RILP. Our data in cultured rat and mouse hippocampal neurons of both sexes suggest that endogenous RILP is a functional RAB7A-dependent dynein adaptor for LE motility in dendrites. In addition, it promotes endosome carrier formation. As a consequence of LE transport inhibition, degradative cargos are not cleared normally from dendrites in RAB7A-L8A. Surprisingly, lysosomal fusion and somatic degradation do not require RAB7A-RILP interactions. Despite the normal degradation, dendrite arborization is impaired in RAB7A-L8A expressing neurons, demonstrating that dendrite morphology defects are separable from degradation blockade. This indicates that normal dendrite growth/maintenance is dependent on sustained RAB7A/RILP-dependent LE transport.
Int J Neurosci
· 2026 Jun · PMID 42240303
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Alzheimer's disease (AD) is a progressive neurodegenerative disorder that severely affects memory, cognition, and behavioral functions, making early and accurate stage classification essential for timely clinical interve...Alzheimer's disease (AD) is a progressive neurodegenerative disorder that severely affects memory, cognition, and behavioral functions, making early and accurate stage classification essential for timely clinical intervention and treatment planning. Conventional MRI-based diagnostic approaches are often limited by noise sensitivity, manual interpretation, and insufficient capability to model complex non-linear neuroimaging relationships across multiple disease stages. To address these limitations, this paper proposes a novel Hybrid Quantum-Classical Spike-Driven Network optimized with the Bobcat Optimization Algorithm(HQSDNet-BOA)for automated multistage AD classification using MRI data. The suggested framework introduces an integrated architecture that combines Square Root Sage-Husa Adaptive Robust Kalman Filtering(SRS-HARKF)for adaptive noise suppression and covariance stabilization, Graph-Enhanced Fuzzy Clustering (GEFC)for structurally consistent brain tissue segmentation, and a Hybrid Structural Graph Attention Network(HSGAN)for learning discriminative local-global anatomical representations. Moreover, Hybrid Quantum-Classical Spike-Driven Network (HQSDNet), which incorporates quantum convolutional learning, spike-driven transformers, and structural attention schemes, is designed to precisely identify nonlinear and spatial-temporal disease patterns. Bobcat Optimization Algorithm (BOA) is used for optimizing network parameters in real-time to ensure convergence efficiency and computational optimization. This study was performed using two datasets: ADNI (5,300 images representing five disease stages) and OASIS-3 (3,712 images representing three cognitive classes). The suggested HQSDNet-BOA yielded improved classification results with 98.8% accuracy, 98.0% precision, 98.5% recall, and 98.25% F1-score when applied to the ADNI dataset and outperformed the existing techniques in terms of computational speed. The obtained results confirm that the suggested framework provides a robust, efficient, and clinically relevant solution for accurate AD stage prediction and neuroimaging-based diagnostic support.
Fahmy MA, Abdel-Aal AA, Hassan SI
… +2 more, Shalaby MA, Esmat M
BMC Neurosci
· 2026 Jun · PMID 42237095
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Cerebral toxoplasmosis is a common opportunistic parasitic infection of the CNS caused by the Toxoplasma gondii parasite. Host immunosuppression can affect disease outcomes. To explore the changes in the cerebral cortica...Cerebral toxoplasmosis is a common opportunistic parasitic infection of the CNS caused by the Toxoplasma gondii parasite. Host immunosuppression can affect disease outcomes. To explore the changes in the cerebral cortical ultrastructure accompanying the infection in different immune-altered models and to find an effective treatment against the infection, we tested the possible therapeutic effect of clofazimine (CFZ) (the FDA-approved antimycobacterial drug) against the infection using 60 male CD1 Swiss Albino mice divided into 6 groups: 3 dexamethasone (DEX)- treated groups (DEX-only, DEX-infected, and DEX-infected-treated), and 3 streptozotocin (STZ)-induced type 1 diabetic groups (STZ-only, STZ-infected, STZ-infected-treated). The worst ultrastructural changes were observed in the diabetic and diabetic-infected groups, characterized by a significant increase in neuronal apoptotic and necrotic nuclei (P < 0.05) and changes in the numbers and structure of glial cells compared to the DEX and DEX-infected groups. CFZ (at a dose of 10 mg/kg/day for 3 days starting on 45th day post infection) significantly improved cortical neuronal ultrastructural changes in both models (P < 0.05), reduced microglial numbers, increased astrocyte numbers, and restored brain capillary integrity and axonal growth, in addition to significantly reducing mature cyst numbers in both models (P < 0.05). However, the drug didn't reduce the number of atrophic and necrotic cysts in the infected-treated groups. So, in our study, CFZ showed preclinical promise in treating experimental cerebral toxoplasmosis and reducing the parasitic cyst burden, highlighting the adverse impact of the host's altered immune status on brain tissue and the course of the infection, especially in diabetes.
Neurons in basolateral amygdala (BLA) encode positive and negative valence. However, many additional variables must be represented to describe all aspects of emotional states. To investigate how BLA encodes these states,...Neurons in basolateral amygdala (BLA) encode positive and negative valence. However, many additional variables must be represented to describe all aspects of emotional states. To investigate how BLA encodes these states, we presented mice with conditioned stimuli that elicited two behavioral responses: tremble and ingress into a burrow, reflecting fear and flight to safety, respectively. BLA inactivation eliminated several aspects of differential responses to aversive versus neutral stimuli without eliminating tremble and ingress themselves, consistent with BLA's encoding valence not motor commands. However, individual neurons rarely represented only valence, exhibiting, instead, mixed selectivity for stimulus identity, stimulus valence, tremble and/or ingress. Despite prevalent mixed selectivity, population activity sometimes realized a representational geometry that conferred two computational properties defining specialized readouts: generalization across conditions and no interference between readouts of different variables. These specialized readouts enable output responses to depend on one specific variable and to remain unaffected by the others.
Vagus nerve stimulation (VNS) alleviates pain, yet the underlying neural mechanisms remain elusive. Furthermore, the caudal nucleus of the solitary tract (cNTS) receives vagal and somatic inputs, but how it transforms pa...Vagus nerve stimulation (VNS) alleviates pain, yet the underlying neural mechanisms remain elusive. Furthermore, the caudal nucleus of the solitary tract (cNTS) receives vagal and somatic inputs, but how it transforms pain signals into behavior and how VNS modulates this processing remain unclear. Here we identified a population of cNTS neurons projecting to the periaqueductal gray (PAG) (cNTS) as a critical node for VNS-dependent suppression of pain and negative affect in mice. Optogenetic activation of cNTS neurons recapitulated pain behavior. These neurons exhibited modality-specific encoding of pain and predictive signals after learning. Inhibition of spinal input-defined cNTS neurons reduced mechanical, but not thermal, nociception. Notably, VNS selectively dampened pain-evoked cNTS activity by recruiting local inhibition and attenuated pain-evoked dopamine reductions in the nucleus accumbens through cNTS. Our findings establish a brainstem pathway with a previously unrecognized role in VNS modulation of pain and negative affect, providing insights for targeted neuromodulation in pain management.
Azbukina N, He Z, Lin HC
… +12 more, Santel M, Kashanian B, Maynard A, Török T, Okamoto R, Nikolova MT, Seimiya M, Kanton S, Brösamle V, Holtackers R, Camp JG, Treutlein B
Patterning of the neural tube establishes midbrain and hindbrain structures that coordinate motor movement, process sensory input and integrate cognitive functions. Cellular impairment within these structures underlies d...Patterning of the neural tube establishes midbrain and hindbrain structures that coordinate motor movement, process sensory input and integrate cognitive functions. Cellular impairment within these structures underlies diverse neurological disorders, and in vitro organoid models promise inroads to understanding development and modeling disease. Here, we use paired single-cell transcriptome and accessible chromatin sequencing to map cell composition and regulatory mechanisms in organoid models of midbrain and hindbrain. We find that existing midbrain organoid protocols generate ventral and dorsal cell types, covering regions including floor plate, dorsal and ventral midbrain and adjacent hindbrain regions. Gene regulatory network inference and transcription factor perturbation resolve mechanisms underlying neuronal differentiation. A single-cell multiplexed patterning screen identifies morphogen concentrations that expand existing organoid models, including conditions generating medulla glycinergic neurons and cerebellum glutamatergic subtypes. Together, the multi-omic atlas and morphogen screen reveal morphogen-regulon relationships guiding region-specific progenitor differentiation towards diverse neuron types of the posterior brain.
The pulvinar is a large, multisensory thalamic hub with distinct subregions and widespread cortical connectivity. This widespread connectivity is thought to regulate the flow of information across the cortex, and recent...The pulvinar is a large, multisensory thalamic hub with distinct subregions and widespread cortical connectivity. This widespread connectivity is thought to regulate the flow of information across the cortex, and recent studies have leveraged the pulvinar for neuromodulation. The evolutionary expansion, particularly for the medial pulvinar in humans, highlights the importance to study selective pulvinar influence across the human cortex. We therefore used single-pulse electrical stimulation to causally map the influence of pulvinar on the cortex in 30 patients (14 female) implanted with stereotactic EEG for drug-resistant epilepsy monitoring. In individual subjects, we found that stimulation of the lateral pulvinar influenced striate and extrastriate regions, while ventral-medial pulvinar stimulation preferentially influenced lateral temporal cortices. Across all subjects, the dorsomedial pulvinar stimulation influenced the parietal cortex. Furthermore, these effects were captured by a compact set of large-scale cortical gradients, including outputs along a dorsal-ventral, anterior-posterior, and medial-lateral pulvinar axis. These findings demonstrate that pulvinar subregions influence select cortical networks in humans. These maps of influence may guide further development of pulvinar subregions as distinct neuromodulation targets.
This Viewpoint argues that understanding how the brain controls behavior requires an explicitly evolutionary framework. The mammalian brain did not emerge through the replacement of earlier circuits with perfect alternat...This Viewpoint argues that understanding how the brain controls behavior requires an explicitly evolutionary framework. The mammalian brain did not emerge through the replacement of earlier circuits with perfect alternatives but rather through the elaboration of existing circuits along with the addition of new ones, yielding a hierarchical architecture in which many ancient spinal and brainstem circuits remain functionally essential. In this context, cortex does not directly control behavior but exerts its influence via layer 5 projections to evolutionarily older subcortical motor centers. This view challenges the prevailing corticocentric bias in neuroscience, which often treats cortex as a largely self-contained computational system. We propose that key functions such as attention and efference copy are best understood within this layered organization. Attention may reflect competitive filtering of corticofugal outputs at subcortical bottlenecks, while efference copies arise naturally from branching motor pathways distributed across hierarchical levels that reflect evolutionary history. Crucially, these principles expose important limitations in current computational models, which typically omit subcortical circuitry and treat motor output as a terminal stage of processing. An evolutionary perspective instead demands models that integrate cortex with spinal, brainstem, and midbrain systems as interacting components of a unified sensorimotor hierarchy. Incorporating these constraints will be essential for developing biologically grounded theories of brain function.
Lagomarsino VN, Robinson A, Mitchell PE
… +12 more, Jiang M, Hutchinson LE, Sekela JJ, Caron P, Gehris MK, Navas KI, Duarte-Silva M, Netherland M, Hasan NA, Guillemette C, Redinbo MR, Rao M
The coordinated transit of intestinal contents is crucial for digestion and host defense, and is regulated by cross-talk between neural circuits, the muscular gut wall and luminal factors. Here we show that androgen sign...The coordinated transit of intestinal contents is crucial for digestion and host defense, and is regulated by cross-talk between neural circuits, the muscular gut wall and luminal factors. Here we show that androgen signaling to Nos1 enteric neurons and Scn10a spinal afferent neurons is required for normal intestinal transit in mice and is microbiome dependent. Microbial depletion with antibiotics abolished androgen receptor expression in enteric neurons, diminished serum testosterone and caused dysmotility. Androgens were necessary for antibiotics to affect transit and partly sufficient to rescue dysmotility. Nos1 neurons upregulate androgen receptor upon puberty in parallel with shifts in fecal bacterial beta-glucuronidase (GUS) enzymes that can deconjugate steroid glucuronides in mice and humans. Intracolonic administration of a GUS enzyme found to metabolize androgen glucuronides was sufficient to restore neuronal androgen signaling in microbe-depleted mice. Thus, gut microbial reactivation of host-excreted androgens via GUS enzymes represents a dynamic microbe-host interaction that is essential for peripheral nervous system function in homeostasis.
Int J Neurosci
· 2026 Jun · PMID 42230331
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AIM: This study aimed to evaluate whether early Bobath-based neurorehabilitation improves motor and functional recovery in patients with acute ischemic stroke and moderate-to-severe hemiparesis after anterior-circulation...AIM: This study aimed to evaluate whether early Bobath-based neurorehabilitation improves motor and functional recovery in patients with acute ischemic stroke and moderate-to-severe hemiparesis after anterior-circulation mechanical thrombectomy. METHODS: We conducted a single-center retrospective propensity score-matched cohort study comparing early Bobath-based neurorehabilitation with conventional rehabilitation in AIS patients with moderate-to-severe hemiparesis after anterior-circulation mechanical thrombectomy. Patients aged ≥18 years initiated rehabilitation within 30 days after the procedure, and complete discharge and follow-up data were required for inclusion in the matched cohort. The primary outcome was change in Fugl-Meyer Assessment (FMA) motor score from baseline to discharge. Secondary outcomes included Modified Barthel Index (MBI), Modified Ashworth Scale (MAS), modified Rankin Scale (mRS), quality of life, and safety outcomes during 12-month follow-up. RESULTS: After matching, 206 patients (103 per group) were included. At discharge, the Bobath group showed greater improvement in motor function and daily living ability than the conventional group (adjusted mean difference: FMA 5.7 points, 95% CI 3.4-8.0; MBI 6.6 points, 95% CI 4.0-9.3; both < 0.001). Improvements remained significant at 3 months but not at 12 months. Functional independence (mRS ≤2) at 3 months was more frequent in the Bobath group (82.5% vs 73.8%; = 0.05). Complication rates were similar between groups. CONCLUSIONS: Early Bobath-based neurorehabilitation is associated with better short-term motor and functional recovery without increased adverse events after mechanical thrombectomy. The between-group differences attenuated by 12 months; therefore, further multicenter prospective studies are needed to confirm durability and long-term benefit.
Cortical areas involved in self-motion perception process cues from multiple sensory modalities, primarily visual and vestibular, alongside choice-related activity. Neurons in these regions often respond to combinations...Cortical areas involved in self-motion perception process cues from multiple sensory modalities, primarily visual and vestibular, alongside choice-related activity. Neurons in these regions often respond to combinations of these factors-demonstrating a high degree of mixed selectivity. Moreover, self-motion is inherently dynamic, with each cue-visual and vestibular-comprising a mix of distinct motion signals, such as velocity and acceleration, that evolve over time. Here, we developed a time-varying targeted dimensionality reduction method to expose these dynamic motion and choice-related signals in neuronal populations. We applied this approach to recordings from the ventral intraparietal cortex (VIP), dorsal medial superior temporal cortex (MSTd), and parietoinsular vestibular cortex (PIVC), in six male rhesus macaques, performing a task of heading discrimination. Distinct configurations of dynamic signals were seen in the population activity across the different cortical areas. VIP exhibited all components-namely, velocity and acceleration, for visual and vestibular cues, along with strong choice-related signals that rose early and remained elevated throughout the stimulus period, well before the choice was reported. In contrast, MSTd and PIVC had weaker and later choice-related activity. MSTd primarily exhibited visual signals (velocity more than acceleration) with weak vestibular signals. PIVC predominantly exhibited vestibular signals (velocity and acceleration), yet visual signals were nonetheless present. The distinct configurations of time-varying parameters across VIP, MSTd, and PIVC likely reflect different functional specializations in heading discrimination.
Long-term potentiation (LTP) induces presynaptic bouton enlargement and a reduction in the number of synaptic vesicles. To understand the relationship between these events, we performed 3D analysis of serial section elec...Long-term potentiation (LTP) induces presynaptic bouton enlargement and a reduction in the number of synaptic vesicles. To understand the relationship between these events, we performed 3D analysis of serial section electron micrographs in hippocampal area CA1 from male rats, 2 h after LTP induction. We observed a high vesicle packing density in control boutons, contrasting with a lower density in most LTP boutons. Notably, the summed membrane area of the vesicles lost in low-density LTP boutons is comparable to the surface membrane required for the observed bouton enlargement when compared with high-density control boutons. These novel findings suggest that presynaptic vesicle density provides a new structural indicator of LTP that supports a local mechanism of bouton enlargement.
Neuroscience
· 2026 Jun · PMID 42229831
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Parkinson's disease (PD) is a progressive neurodegenerative disorder lacking established clinical biomarkers. We performed an exploratory multi‑omics analysis of transcriptome and proteome data from small PD and control...Parkinson's disease (PD) is a progressive neurodegenerative disorder lacking established clinical biomarkers. We performed an exploratory multi‑omics analysis of transcriptome and proteome data from small PD and control cohorts at Huaihe Hospital of Henan University. Using two local datasets, we identified 124 differentially expressed genes (DEGs) and 28 proteins, then performed protein‑protein interaction (PPI) and gene set variation analysis (GSVA). After intersecting with 2,964 DEGs from Gene Expression Omnibus (GEO) Dataset 3, we obtained a 28‑gene panel. Potential markers were prioritized via random forest (RF), support vector machine (SVM) and principal component analysis (PCA), and evaluated in external GEO data, clinical serum samples and a 1‑methyl‑4‑phenyl‑1,2,3,6‑tetrahydropyridine (MPTP)‑induced PD mouse model. PPI highlighted C‑X‑C motif chemokine ligand 1 (CXCL1), C‑X‑C chemokine receptor type 4 (CXCR4), S100 calcium‑binding protein A12 (S100A12) and C‑X‑C motif chemokine ligand 11 (CXCL11) as hub genes. GSVA indicated upregulated cardiac muscle contraction and oxidative phosphorylation (OXPHOS). C‑C motif chemokine ligand 4 (CCL4), CKLF like MARVEL transmembrane domain containing 2 (CMTM2), tudor domain containing 6 (TDRD6), potassium voltage‑gated channel subfamily S member 1 (KCNS1) and member RAS oncogene family (RAB15) were identified as candidate markers. They showed consistent expression changes in clinical samples and mice. Immune infiltration differed in B cells, CD8 + T cells and natural killer (NK) cells. LY‑303511 and HC‑toxin were predicted as candidate compounds. These five genes represent preliminary candidate biomarkers for PD; however, further validation in larger independent cohorts is warranted for clinical translation.