Search Results (185)

The structures predicted by AlphaFold can provide unprecedented opportunities for docking screens; however, experimentally validated examples of using the apo-form are limited. This study reports novel chemotype inhibitors targeting the leucine-rich repeat kinase 2 (LRRK2) kinase domain through a docking screen using one of the ensemble structures starting from the template deposited by AlphaFold2. The MODELLER software generated the ensemble. The conformer that showed the best early enrichment of true positives with the mixture of known ligands and their property-matched decoys was selected. The docking screen against approximately 1.3 million small molecules and enzyme-based assays with the LRRK2 kinase domain followed. We selected 17 molecules, excluding those similar to all known kinase inhibitors. Combined with analogs-by-catalog, ten new small molecules with Ki values below 15 μM were discovered, including one sub-μM inhibitor. To test selectivity, enzyme assays with a mutant and six additional kinases, including known off-targets of existing LRRK2 inhibitors, were performed using three inhibitors. The data suggest that the novelty in chemical structure may be insufficient for providing selectivity. Our approach is generally applicable to cases where information on known binders is available but experimental structure is not. Full article

Leucine-rich-repeat kinase 2 (LRRK2) is a multidomain protein highly expressed in immune cells and implicated in the regulation of immune functions including immune signaling, cytokine release and autophagy. LRRK2 is one of the therapeutic targets in Parkinson’s Disease (PD). Aberrant activation of LRRK2 can also contribute to intestinal inflammation, mainly in inflammatory bowel disease (IBD). Hence the modulation of LRRK2 may influence gut inflammation providing an improvement in disease outcomes. Over the years, microRNAs (miRNAs) have acquired much attention thanks to their potential as therapeutic targets in several pathological conditions, including inflammatory disorders. In this study, we aimed to examine the ability of miR-369-3p in the modulation of autophagy targeting LRRK2 expression. Bioinformatics analysis revealed that Lrrk2 is a target gene of miR-369-3p, and LRRK2 expression was increased in ulcerative colitis patients compared with that in a healthy control. In in vitro analysis, we validated that mimic transfection with miR-369-3p in Raw264.7 significantly reduced the expression of LRRK2 both in basal and inflammatory conditions. Moreover, the inhibition of LRRK2 limited the nuclear translocation of Nuclear factor kappa B (NF-κB) induced by lipopolysaccharide (LPS) stimulation. In turn, we found that, in inflammatory conditions, the intracellular increase in miR-369-3p precluded the inhibition of autophagy by LRRK2 by restoring autophagy marker light chain 3 (LC3)II/I ratio, BECLIN-1 and decreasing p62 expression. Furthermore, we detected that the upregulation of miR-369-3p decreased the release of pro-inflammatory mediators Tumor necrosis factor (TNF), C-C motif ligand 2/Monocyte chemoattractant protein-1 (CCL2/MCP-1), C-C motif ligand 3/Macrophage inflammatory protein-1 alpha (CCL3/MIP-1α) and C-C motif ligand 5/Regulated on activation, normal T-cell expressed and secreted (CCL5/RANTES) and increased the anti-inflammatory cytokine interleukin 10 (IL-10) in response to LPS. This study supports the anti-inflammatory potential of miR-369-3p in immune cells and suggests the potential of miR-369-3p as a therapeutic agent in the treatment of acute intestinal inflammatory conditions such as ulcerative colitis. Full article

Alzheimer’s (AD) and Parkinson’s disease (PD) are prominent neurodegenerative disorders characterized by early synaptic loss, which correlates more closely with clinical symptoms than neuronal death. This synaptic impairment is primarily driven by disruptions in synaptic vesicle (SV) trafficking, a critical process for maintaining synaptic integrity through a tightly regulated cycle involving clustering, docking-priming, Ca²⁺-triggered fusion, and endocytosis. In AD, amyloid-β (Aβ) oligomers interfere with SNARE-mediated fusion and endocytosis, while hyperphosphorylated tau obstructs vesicle mobility and docking, resulting in cumulative toxicity that aggravates SV defects. Conversely, in PD, α-synuclein (α-syn) aggregation alters vesicle clustering, membrane fusion, and recycling, and these effects are further influenced by Leucine-rich repeat kinase 2 (LRRK2)-Rab-related trafficking defects and the selective vulnerability of dopaminergic terminals. Different from previous reviews that address synaptic dysfunction in a broader manner, the present review is specifically organized around the SV trafficking cycle and compares both shared presynaptic endpoints and disease-specific upstream mechanisms in AD and PD. In addition, recent mechanism-oriented therapeutic strategies are summarized. This vesicle-cycle-centered perspective may provide a clearer framework for understanding presynaptic pathology and for guiding the development of earlier and more targeted interventions. Full article

Mutations in leucine-rich repeat kinase 2 (LRRK2) are among the most common genetic causes of Parkinson’s disease (PD), yet substantial heterogeneity exists among pathogenic variants. How mutations in distinct functional domains of LRRK2 differentially perturb cellular homeostasis remains incompletely understood. Here, we compared two pathogenic LRRK2 mutations—G2019S in the kinase domain and I1371V in the GTPase domain—across multiple cellular models, including SH-SY5Y and U87 cells, and healthy human iPSC-derived floor plate cells. We demonstrate that the I1371V mutation induces markedly more severe cellular dysfunction than G2019S. I1371V-expressing cells exhibited elevated LRRK2 autophosphorylation at S1292 and robust hyperphosphorylation of Rab8A and Rab10, indicating enhanced downstream signaling. These alterations impaired sterol trafficking, leading to selective depletion of membrane cholesterol without changes in total cellular cholesterol. Consequently, I1371V cells displayed increased membrane fluidity, disrupted microdomain organization, altered membrane topology, reduced caveolin-1 expression, and impaired dopamine transporter surface expression and dopamine uptake. Lipidomic profiling further revealed a broad disruption of lipid homeostasis, including reductions in cholesteryl esters, sterols, sphingolipids, and glycerophospholipids, whereas G2019S cells showed comparatively modest changes. Pharmacological intervention revealed mutation-specific responses, with the non-selective LRRK2 modulator GW5074 outperforming the kinase-selective inhibitor MLi-2 in restoring Rab8A phosphorylation, membrane integrity, and dopaminergic function. Collectively, these findings identify membrane lipid dysregulation as a central cell biological mechanism in LRRK2-associated PD and underscore the importance of variant-specific therapeutic strategies. Full article

Parkinson’s disease (PD) is a progressive and heterogeneous neurodegenerative disorder and one of the fastest-growing causes of neurological disability worldwide. Although historically defined by motor manifestations resulting from nigrostriatal dopaminergic degeneration, PD is now recognized as a multisystem disorder. Non-motor features—including autonomic dysfunction, neuropsychiatric symptoms, cognitive impairment, and sleep-related disorders—frequently precede motor onset by years or even decades, delineating a clinically meaningful prodromal phase. The aetiology of PD reflects a complex interplay between genetic susceptibility and environmental exposures. Approximately 20% of cases are linked to identifiable pathogenic variants, most commonly in LRRK2, GBA1, and SNCA, whereas the majority arise from cumulative interactions among environmental factors, lifestyle determinants, and common genetic risk variants rather than from single causal mechanisms. Despite substantial advances in understanding disease biology, current therapies remain fundamentally symptomatic. Dopaminergic pharmacotherapy and device-aided interventions improve motor function and, in selected contexts, functional outcomes, but they do not modify disease progression. Non-motor symptoms remain a dominant driver of disability and reduced quality of life. Recent conceptual frameworks propose redefining PD as a biologically defined α-synucleinopathy. Emerging biomarkers, including α-synuclein seed amplification assays in cerebrospinal fluid and peripheral tissues, offer unprecedented opportunities to define biological disease, enable early detection, and stratify patients. However, biomarker positivity currently informs diagnosis and classification rather than prognostication or therapeutic selection, and validated intermediate endpoints linking biomarker change to sustained functional benefit remain lacking. Consequently, translation into disease-modifying therapies has been constrained by late-stage intervention, reliance on clinically defined populations, limited trial generalizability, and marked global inequities in access to advanced diagnostics and treatments. This narrative review synthesizes current evidence on PD epidemiology, diagnosis, aetiology, progression, and treatment, emphasizing gene–environment interactions, convergence on shared pathogenic pathways, limitations of existing therapeutic paradigms, and the as-yet unrealized potential of biologically informed precision care. Full article

Parkinson’s disease (PD) is a progressive neurodegenerative disorder shaped by genetic factors such as LRRK2 and GBA1 mutations, as well as dietary and metabolic influences. Food-derived plasma metabolites—including caffeine, paraxanthine, trigonelline, piperine, and sitosteryl hexoside—have emerged as promising, accessible biomarkers for early detection, progression monitoring, and therapeutic targeting, yet their longitudinal behavior and genetic interactions remain insufficiently characterized. Using the Parkinson’s Progression Markers Initiative (PPMI) cohort (n = 455; 303 PD patients, 152 controls), we quantified plasma levels of these metabolites by quantitative LC-MS/MS with batch correction, examining sporadic PD and genetically defined subgroups (LRRK2-PD [PDL], GBA1-PD [PDG], dual-mutation PD [PDGL], and prodromal equivalents). Baseline one-way ANOVA showed significantly lower caffeine and paraxanthine in PDL (p = 0.0467, p = 0.0178) and PDG (p = 0.0408), reduced piperine in PDL (p = 0.0009), PDG (p = 0.0257), and prodromal LRRK2 (p = 0.0168), and elevated sitosteryl hexoside in PDG (p = 0.0184). Longitudinal regression analyses revealed that in sporadic PD, caffeine negatively correlated with MDS-UPDRS parts I (β = −2, p = 0.0475) and III (β = −7.2, p = 0.007), trigonelline declined over time and was inversely associated with part III (β = −1.7, p = 0.0069), and sitosteryl hexoside negatively correlated with parts II (β = −68.3, p = 0.042) and III (β = −74.1, p = 0.0425). In PDL, sitosteryl hexoside inversely correlated with part I (β = −54.2, p = 0.0049), while in PDGL, paraxanthine showed negative associations with part II (β = −18.5, p = 0.00327). These findings demonstrate subgroup-specific alterations in food-derived metabolites and consistent inverse associations with PD severity, supporting their potential as non-invasive biomarkers, particularly in LRRK2/GBA1 mutation carriers, and highlighting the need for longitudinal validation and dietary intervention trials to advance personalized PD management. Full article

Background/Objective: Genetic factors contribute significantly to Parkinson’s disease (PD), especially in cases with early onset or positive family history. However, previous investigations of the genetic landscape in PD populations were mainly based on targeted genotyping. The aim of this study was to investigate the prevalence of pathogenic variants in known PD-associated genes in a series of Swedish PD patients. Methods: We performed whole-exome sequencing on 285 PD probands from southern Sweden. Our series was enriched for patients with early disease onset or positive family history. We focused on 44 genes previously linked to PD. Results: We identified a CHCHD2 p.(Phe84LeufsTer6) frameshift variant in two unrelated patients and report the first PD case of Swedish ancestry carrying the VPS35 p.(Asp620Asn) variant. Additionally, in one patient each, we found an SNCA duplication, an SNCA p.(Ala53Thr) variant, and a LRRK2 p.(Gly2019Ser) variant. Thus, only 2.1% (n = 6) of patients in this series had Mendelian monogenic PD forms. In addition, forty-three patients carried variants in GBA1, including T369M, which may lack disease-association in our population (n = 12); E326K (n = 22), which is classified as a PD risk variant; as well as N370S (n = 3), R329H (n = 3), S107L (n = 1), and L444P (n = 1), with one patient harboring both T369M and E326K. Pathogenic variants in ARSA, ATP7B, and PRKN genes were also detected in heterozygote form, but their role in PD remains uncertain. Conclusions: Monogenic forms of PD are rare in southern Sweden, even among the familial and early-onset PD patients that were overrepresented in our study. Our findings highlight the genetic diversity in Swedish PD patients and identify key variants for further functional and clinical studies. Full article

Growth and carcass traits are key economic traits in beef cattle production, and identifying their associated genetic markers is crucial for improving breeding efficiency. Charolais cattle, as a superior beef breed, exhibit excellent performance in growth rate and meat production. The aim of this study was to utilize the preferred high-coverage whole-genome resequencing (hcWGS) as a replacement for single nucleotide polymorphism (SNP) chips to identify significant SNPs and candidate genes associated with growth (body weight, body height, cross height, body length, and chest measurement across different growth stages) and carcass traits (live backfat thickness and eye muscle area at 18 months) in 240 Charolais cattle, thereby providing guidance for beef cattle breeding. Through hcWGS (approximately 13× coverage) and quality control, 4,088,633 SNPs were identified and subsequently used for genetic analyses. Through FarmCPU-based genome-wide association studies, 196 potentially significant SNPs associated with growth traits and 29 SNPs with carcass traits were identified. Annotation analyses revealed 353 candidate genes (such as RBM33, KCTD17, PTHLH, RAC2, CHD6, TRDN, WBP1L, TLL2, CH25H, and ST13) linked to growth traits and 26 candidate genes linked to carcass traits (such as CHST11, LRRK2, RIOK2, and INTS10). Additionally, three SNPs (g.8674692C>G, g.54418624G>T, and g.71085551G>A) were validated via polymerase chain reaction–restriction fragment length polymorphism (PCR-RFLP), enabling efficient marker-assisted selection. Furthermore, eight SNPs in the Acyl-CoA oxidase 1 (ACOX1) gene were found to be associated with growth and backfat thickness traits. These findings provide valuable preliminary insights into the genetic mechanisms underlying growth and carcass traits in Charolais cattle, facilitating genome-assisted breeding. Full article

Background/Objectives: Leucine-rich repeat kinase 2 (LRRK2) is an enzyme implicated in Parkinson’s disease (PD) and a potential therapeutic target. LRRK2 PET radioligands could therefore function as imaging biomarkers for PD and as tools to measure enzyme occupancy of novel therapeutic candidates. This study aimed at developing novel radioligands for imaging using positron emission tomography (PET). Specific objectives were to synthesize fluorine-18-labeled pyrrolopyridine 1 ([¹⁸F]1), pyrrolo-pyrimidine 2 ([¹⁸F]2), as well as carbon-11-labeled pyrrolo-pyrimidine 3 ([¹¹C]3), and examine their binding specificity, using in vitro autoradiography (ARG) and in vivo positron emission tomography (PET) imaging in non-human primates (NHPs). Methods: Radiolabeling was achieved either by classical one-step fluorine-18 nucleophilic substitution reaction or by methylation using carbon-11 methane. [¹⁸F]1 and [¹⁸F]2 were tested in NHP and human whole-hemisphere ARG experiments. PET imaging was performed in cynomolgus monkeys. Radiometabolites were measured in monkey plasma using gradient HPLC. Results: The results demonstrated successful radiolabeling of all three ligands. In ARG studies, both [¹⁸F]1 and [¹⁸F]2 displayed binding in brain slices from NHP and human samples. The binding of [¹⁸F]1 was blocked by cold Compound 1 and structurally distinct Compound 3, but not by the structurally distinct LRRK2 inhibitor PFE-360. On the other hand, the binding of [¹⁸F]2 was blocked by PFE-360 in certain regions of the brain, indicating some level of specific binding to LRRK2. All three ligands showed relevant brain uptake (>3%ID), with highest uptake being observed for [¹⁸F]1, particularly in the thalamus. In contrast, brain uptake of [¹⁸F]2 and [¹¹C]3 was evenly distributed across all brain regions. No blocking effect of [¹⁸F]1 was observed after pretreatment with the structurally distinct LRRK2 inhibitors PFE-360 (0.5 mg/kg, iv) and GEN-7915 (40 mg/kg). Conclusions: PET imaging indicated a low in vivo specific binding of the radioligands in the cynomolgus monkey brain, suggesting that the radioligands are not suitable for LRRK2 imaging in vivo with PET. This study emphasizes the challenges in the development of PET radioligands for imaging LRRK2 and the need for additional work to achieve this goal. Full article

Background/Objectives: Prior studies have reported a complex interplay between Parkinson’s disease (PD) and malignancy. Although patients with PD often present a lower general risk for several types of cancer, some forms—including melanoma—show elevated frequency. The present work aimed to evaluate the occurrence of cancers other than melanoma among individuals with sporadic and genetic PD. Methods: We examined medical histories from 1888 participants with PD and 438 healthy controls (HCs) using the Parkinson’s Progression Markers Initiative (PPMI) dataset, with a focus on neoplastic disease. In cases with positive cancer history, genetic information was additionally assessed [carriers of mutations in the most prevalent PD-related genes were evaluated]. Results: Our results demonstrate that cancer incidence was antecedent to PD diagnosis for the majority of PD patients, while the most common cancer types apart from malignant melanoma were non-melanoma skin cancer and prostate cancer. Conclusions: Regarding genetic PD patients, the most common cancer types in the LRRK2 and GBA1 groups were skin cancer and lymphoma, while PRKN/PARK2 carriers appeared with an overall increased incidence of cancer. No statistically significant results were observed comparing cancer incidence in PD patients to that in healthy control individuals. Interesting results were obtained by dividing the patients by gender, showing increased cancer risk in female PD patients and female LRRK2 carriers, along with increased breast cancer risk in female PD patients compared to healthy controls. Full article

The LRRK2+ SAA− cohort of Parkinson’s disease (PD), characterized by the absence of hallmark α-synuclein pathology, remains under-explored. This limits opportunities for early detection and targeted intervention. This study analyzes data from this under-characterized subgroup and compares it with the LRRK2+ SAA+ cohort using longitudinal data from the Parkinson’s Progression Markers Initiative (PPMI). The PPMI dataset includes 115 LRRK2+ patients (70 SAA+, 45 SAA−) across 52 features encompassing clinical assessments, cognitive scores, DaTScan SPECT imaging, and motor severity. DaTScan binding ratios were selected as imaging-based indicators of early dopaminergic loss, while NP3TOT (MDS-UPDRS Part III total score) was used as a gold-standard clinical measure of motor symptom severity. Linear mixed-effects models were then applied to evaluate longitudinal predictors of DaTScan decline and NP3TOT progression, and statistical analyses of group comparisons revealed distinct drivers of symptoms differentiating SAA− from SAA+ patients. In SAA− patients, a decline in DaTScan was significantly associated with thermoregulatory impairment (p-value = 0.019), while NP3TOT progression was predicted by constipation (p-value = 0.030), sleep disturbances (p-value = 0.046), and longitudinal time effects (p-value = 0.043). In contrast, SAA+ patients showed significantly lower DaTScan values compared to SAA− (p-value = 0.0004) and stronger coupling with classical motor impairments, including freezing of gait (p-value = 0.016), rising from a chair (p-value = 0.007), and turning in bed (p-value = 0.016), along with cognitive decline (MoCA clock-hands test, p-value = 0.037). These findings support the hypothesis that LRRK2+ SAA− patients follow a distinct pathophysiological course, where progression is influenced more by autonomic and non-motor symptoms than by typical motor dysfunction. This study establishes a robust, multimodal modeling framework for examining heterogeneity in genetic PD and highlights the utility of combining DaTScan, NP3TOT, and symptom-specific features for early subtype differentiation. These findings have direct clinical implications, as stratifying LRRK2 carriers by SAA status may enhance patient monitoring, improve prognostic accuracy, and guide the design of targeted clinical trials for disease-modifying therapies. Full article

Background/Objectives: Parkinson’s disease (PD) is a neurodegenerative disease that develops with age and is related to a decline in motor function. Studies suggest that the causes may be based on genetic dysfunction including PARK gene mutations and environmental factors. Methods: To explore those factors, we used multivariable logistic regression to obtain odds ratios (ORs) and adjusted ORs by using the All of Us Dataset which contains genomic, blood test, and other environmental data. Results: On Chromosome 12, there were 3709 candidate genetic polymorphisms (GPs) that are associated with PD. Of those GPs, fourteen GPs had high ORs which are similar to the OR of the PARK8 gene G2019S mutation. Of those 3709 GPs, a 2.00-fold change in OR was observed in five GPs located at bases 53,711,362 (OR = 4.86, 95% CI [1.46, 16.18]), 31,281,818 (OR = 4.37, 95% CI [1.02, 18.82]), 101,921,705 (OR = 5.38, 95% CI [1.23, 23.51]), 47,968,795 (OR = 7.82, 95% CI [1.81, 33.83]), and 112,791,809 (OR = 8.05, 95% CI [1.85, 35.05]) by calcium, Vitamin D, and alcohol intake and were statistically significant. Conclusions: The results suggest that the progression of some PD caused by certain GPs can be delayed or prevented by the environmental factors above. In February 2025, All of Us released the CT Dataset v.8 which has a 50% increase in the number of participants. Potentially, it may be possible to research more GPs and environmental factors. In future studies, we would like to explore other environmental factors and GPs on other chromosomes. It is believed that specific GPs may tailor current treatments and qualify patients for clinical trials. Additionally, genetic knowledge may help increase accuracy in clinical trials. Full article

Parkinson’s disease (PD) is a progressive neurological disorder marked by the gradual loss of dopamine-producing neurons in the brain. This neuronal degradation causes motor symptoms such as tremors, stiffness, and slowness of movement. Despite decades of research, current treatments remain limited to symptom management, highlighting the urgent need for deeper insights into PD mechanisms and new therapeutic approaches. Among model organisms, zebrafish (Danio rerio) have emerged as a valuable tool for PD research due to the possibility of genetic manipulation. Zebrafish can be engineered to carry human PD-associated mutations, such as those in α-synuclein, LRRK2, and Parkin, enabling researchers to study the molecular and cellular basis of the disease. Additionally, exposure to neurotoxins like MPTP and paraquat allows scientists to replicate PD-like symptoms in zebrafish, supporting drug screening and behavioural analysis. This review summarises the key advantages and limitations of zebrafish as a model for PD, compares it with rodent models, and discusses recent advances and future directions that may improve translational outcomes in PD therapy and personalised medicine. Full article

Neurodegeneration is intrinsically linked to aging through processes such as oxidative stress, mitochondrial dysfunction, and chronic inflammation. Nuclear factor erythroid 2-related factor 2 (Nrf2) emerges as a central transcription factor regulating these molecular events and promoting cytoprotective responses. In neurodegenerative diseases, notably, frontotemporal dementia (FTD) and Parkinson’s disease (PD), genetic mutations—including MAPT, LRRK2, PINK1, PRKN, and SNCA—have been reported to alter Nrf2 signaling, both in vitro and in vivo. Melatonin, a neurohormone widely known for its strong antioxidant and mitochondria-stabilizing properties, has been shown to activate Nrf2 and restore redox balance in several experimental models of neurodegeneration. Its effects include a reduction in tau hyperphosphorylation, α-synuclein aggregation, and neuroinflammation. While most data are derived from sporadic models of Alzheimer’s disease and PD, emerging evidence supports a role for melatonin in familial forms of FTD and PD as well. Thus, targeting Nrf2 through melatonin may offer a promising approach to mitigating neurodegeneration, especially in the context of mutation-driven pathologies. Further investigation is warranted to explore mutation-specific responses and optimize the therapeutic strategies. Full article

Chronic neuroinflammation plays a crucial role in the progression of neurodegenerative diseases (NDs), including Parkinson’s disease (PD) and Alzheimer’s disease (AD). Leucine-Rich Repeat Kinase 2 (LRRK2), a gene linked to familial and sporadic PD, has been positively associated with neuroinflammation in both in vitro and in vivo systems. These observations suggest that LRRK2 might actively contribute to neuronal damage and degeneration in NDs. Based on these premises, we explored the impact of LRRK2-mediated neuroinflammation on neurons in a PD- and AD-related context. We set up a cellular model composed of human induced pluripotent stem cell (hiPSC)-derived neurons (dopaminergic for PD and cholinergic for AD) exposed to inflamed glial medium [α-synuclein pre-formed fibrils (α-syn pffs) for PD and amyloid-β (Aβ)_1–42 fibrils for AD] for several days. To dissect the effect of neuroinflammation, and specifically, the role of LRRK2, on neuronal functions, we first performed transcriptome analysis, and then, we validated the results at functional levels. Interestingly, we found that LRRK2-dependent neuroinflammation contributes to neuronal dysfunctions and death in both ND contexts and that LRRK2 kinase inhibition prevents these detrimental effects. Overall, our results suggest that lowering neuroinflammation through LRRK2 pharmacological inhibition might limit the progression of NDs and thus be neuroprotective. Full article