National Neuroscience Institute

Parkinson's disease (PD) involves heterogeneous neurodegenerative processes across brain cell types. The cell-type-specific effects of genetic risk remain unclear. We aimed to identify cell-type-specific causal genes for PD and to link genetic risk to molecular mechanisms and therapeutic opportunities. We performed the first cell-stratified Mendelian randomization integrating single-cell expression quantitative trait loci data from eight brain cell types with large PD genome-wide association studies datasets, followed by validation, neuropathological correlation, and postmortem expression analyses. Thirteen significant causal associations for four genes (ARL17A, ARL17B, KANSL1, LRRC37A) were identified across seven cell types, with consistent replication. ARL17A increased risk, whereas ARL17B, KANSL1, and LRRC37A were protective. Gene expression correlated with disease severity and showed cell-type-specific dysregulation. Drug-gene interaction screen highlighted US Food and Drug Administration-approved agents including raloxifene and dorzolamide as potential therapeutic modulators. This study contributed to cell-type-specific genetic mechanisms in PD, linking risk variants to molecular alterations and nominating therapeutic targets. © 2026 International Parkinson and Movement Disorder Society.

Ischemic stroke is a major neurological disorder that is characterized by cognitive decline and sensorimotor impairment. Despite the potential of therapeutic effects and anti-inflammatory properties of medicinal mushrooms, most current research focuses on single-species effects rather than combined formulations. This gap highlights the need to investigate the potential of a combination of medicinal mushrooms named NevG, containing Lignosus rhinocerus, Hericium erinaceus, and Ganoderma lucidum, focusing on their therapeutic effects in the context of ischemic stroke. Forty adult male Sprague-Dawley rats were randomly assigned to five groups (n = 8): normal, MCAO-induced, and NevG in oral doses of 250mg/kg, 500mg/kg, and 1,000mg/kg for 28 days. Ischemia was induced using the Koizumi method and confirmed through triphenyltetrazolium chloride (TTC) staining and mNSS scoring. Cognitive abilities were assessed using the Morris water maze and T-maze tests, and sensorimotor function was evaluated using the open-field, rotarod, and pole tests. Mechanistic analyses involved measuring anti-inflammatory serum cytokine pathways (TNF-α, IL-1β, IL-6, and NF-κβ). NevG significantly reduced infarct volume by 32%-58% compared with the middle cerebral artery occlusion (MCAO) group (p < 0.05). Cognitive performance improved, with a 25%-46% reduction in the Morris water maze (MWM) escape latency (p < 0.01) and an increase in T-maze spontaneous alternation. Sensorimotor functions were enhanced, as evidenced by increases in the open-field test (OFT), rotarod retention time (p < 0.01), and decreased descent time in the pole test. The cresyl violet staining of the neurons in the hippocampus shows improvement in pyramidal cell counts, and the ultrastructural transmission electron microscope (TEM) analysis shows better preservation of the nucleus and mitochondria, intact myelin sheath, and improved axonal integrity. NevG significantly lowered the inflammatory serum cytokine level (p < 0.05) and promoted neuronal survival. NevG demonstrates significant neuroprotective effects in ischemic stroke, achieved through reduced neuroinflammation and improved neuronal survival, indicating its potential as a natural therapeutic agent.

The human midbrain-like organoid (hMLO) is a key model system for investigating pathological features of Parkinson's disease (PD), yet how its molecular landscape relates to cellular vulnerability in PD remains unclear. We performed in-depth single-cell characterization of our previously established hMLO model up to 150 days in vitro. Our hMLOs exhibited physiological cell types and broad topographical patterning, consistent with features of the human fetal midbrain. We further identified four distinct dopamine-producing neurons (DaN) subtypes whose molecular profiles span a key transcriptomic axis in the selective vulnerability of DaNs in PD. Knockout of PARK7, a highly penetrant PD-causing gene, in hMLOs induced cell type-dependent molecular perturbations in mitochondrial activity and synapse biology, and recapitulated PD pathophysiology, including α-synuclein aggregation, Lewy Body-like inclusions, and DaN degeneration with extended culture. This study highlights the utility of our hMLO model in manifesting pathological features and cell type-specific vulnerability, enabling mechanistic studies into PD pathophysiology.

Abstract Freezing of gait (FoG) prediction is clinically meaningful only when warnings arrive sufficiently early for subsequent action. Therefore, we adopt a Freezing Prediction Horizon (FPH) evaluation that reports prediction performance as a function of the warning horizon before onset, making the lead-time versus reliability trade-off explicit. Within this protocol, we develop a Transformer-based predictor with a progressive self-paced learning strategy and evaluate it on a 55-patient clinical dataset and two public datasets. The horizon–performance curves show that Macro-F1 remains stable up to approximately 2.5 seconds before FoG onset in our dataset, after which a gradual decline is observed. This horizon-based characterization replaces single, fixed ahead-of-onset windows with a continuous method that summarizes achievable advanced time at specified accuracy levels. In this way, it offers a principled basis for setting targets in real-time implementationslinking algorithmic early-warning capacity to the lead times that practical systems may require-while remaining compatible with conventional metrics. By centering evaluation on FPH, this study clarifies how far in advance FoG can be predicted with confidence, and it positions horizon-based assessment as a reproducible complement to standard reporting for future work on deployable FoG prediction. Ultimately, quantifying advance warning is a prerequisite for prevention-oriented use, by indicating whether sufficient time can be reserved for cueing prior to onset.

Although multiple cellular pathways have been implicated in α-Synuclein (α-syn)-associated Parkinson’s disease (PD), the role of lipid metabolism remains elusive. In this study, we identify Drosophila mino, which encodes the mitochondrial isoform of the lipid synthesis enzyme glycerol 3-phosphate acyltransferase (GPAT), as a potent modifier of α-syn. Silencing the expression of mino significantly suppresses α-syn-induced PD phenotypes in Drosophila, including dopaminergic neuronal loss and locomotion defects as well as circadian rhythm-related activities, whereas mino overexpression yields opposite effects. Mechanistically, we find that mino modulates the levels of mitochondrial reactive oxygen species and lipid peroxidation. Importantly, treatment of α-syn-expressing flies with FSG67, a GPAT inhibitor of glycerol 3-phosphate acyltransferase, reproduces the benefits of mino knockdown. FSG67 also inhibits α-syn aggregation and lipid peroxidation in mouse primary neurons treated with α-syn preformed fibrils. Our study elucidates an important factor contributing to α-syn toxicity and offers a therapeutic direction for PD.

This study challenges the assumption that undiagnosed cognitive impairment (CI) is driven primarily by patient-level barriers like poor awareness. In a population-weighted cohort of 1,856 older Singaporeans, CI prevalence was 24.7% (95%CI 18.8-31.8); yet the undiagnosed rate was high (81.4%, 95%CI 65.6-90.9), especially for mild CI (97.9%, 95%CI 94.1-99.3). This diagnostic gap persisted despite high symptom awareness (81.3%, 95%CI 63.6-91.5) and help-seeking intent (63.3%, 95%CI 47.5-76.7), with informants becoming key as CI worsened. Findings suggest successful public health campaigns have shifted the bottleneck from community awareness to healthcare system capacity, creating an opportunity for a policy shift to meet rising demand for diagnosis - by empowering primary care with efficient case-finding tools, formalizing integrated diagnostic pathways, and establishing channels for family informants' involvement. From these findings, we conceptualized a 'paradox of success' model, providing a framework for other health systems to adapt policy as public engagement grows.

Sjögren’s disease (SjD) is a chronic autoimmune connective tissue disorder primarily affecting the salivary and lacrimal glands. Extra-glandular involvement may occur, sometimes preceding the diagnosis of SjD or in the absence of sicca symptoms, contributing to diagnostic delay. Central nervous system (CNS) manifestations have been reported in SjD, though establishing a causal relationship is challenging given possible overlapping neuroinflammatory and autoimmune aetiologies.We report two patients who presented with acute encephalitis and new-onset refractory status epilepticus (NORSE), in whom features supportive of primary SjD were subsequently identified. Both patients underwent extensive evaluation that excluded infectious causes, other systemic autoimmune connective tissue diseases and known autoantibody-mediated forms of autoimmune encephalitis.These cases highlight the importance of considering systemic autoimmune diseases in the evaluation of unexplained encephalitis and NORSE, and support the early use of immunotherapy when an immune-mediated pathology is suspected.