- |||||||||| Journal: LRRK2 Inhibitors as Promising Treatment for Parkinson's Disease. (Pubmed Central) - Nov 20, 2024
Abnormal increases in LRRK2 kinase activity have been identified in both sporadic and familial PD patients, suggesting that inhibiting LRRK2 kinase activity presents a promising avenue for the pursuit of effective PD treatment strategies. In this Viewpoint, we discuss the exciting new insights regarding the development of LRRK2 kinase inhibitors as a treatment for Parkinson's disease.
- |||||||||| Journal: Single-nucleus transcriptomics reveals disease- and pathology-specific signatures in ?-synucleinopathies. (Pubmed Central) - Nov 17, 2024
Finally, exploiting the variable presence and/or severity of ?-synuclein pathology in LRRK2-PD and iPD, we identify cell type-specific signatures associated with ?-synuclein pathology, including a neuronal upregulation of the SNCA gene itself, encoding ?-synuclein. Our findings provide novel insights into the cell-specific transcriptional landscape of the ?-synucleinopathy spectrum.
- |||||||||| Review, Journal: Genetic-based diagnostics of Parkinson's disease and other Parkinsonian syndromes. (Pubmed Central) - Nov 17, 2024
Lastly, we present current clinical trails that are underway for targeted therapies, particularly for GBA1-PD and LRRK2-PD which are the most significant subtypes. While genetic studies alone cannot be diagnostic for PD, proper utilization of genetic screening for PD could improve diagnostic accuracy and predictions for prognosis, guide treatment, and identify individuals that qualify for clinical trials.
- |||||||||| Journal: Pathogenic LRRK2 mutations cause loss of primary cilia and Neurturin in striatal parvalbumin interneurons. (Pubmed Central) - Nov 16, 2024
In addition, in mouse, glial cell line-derived neurotrophic factor-related Neurturin RNA is significantly decreased. These experiments highlight the importance of parvalbumin neurons in cilium-dependent, neuroprotective signaling pathways and show that LRRK2 activation correlates with decreased Neurturin production, resulting in less neuroprotection for dopamine neurons.
- |||||||||| Journal: Macrophage LRRK2 hyperactivity impairs autophagy and induces Paneth cell dysfunction. (Pubmed Central) - Nov 15, 2024
We showed that LRRK2-mediated pro-inflammatory cytokine release from phagocytes impaired Paneth cell function, which was rescued by LRRK2 kinase inhibition through activation of autophagy. Together, these data suggest that LRRK2 kinase inhibitors maintain Paneth cell homeostasis by restoring autophagy and may represent a therapeutic strategy for CD.
- |||||||||| Preclinical, Journal, PD(L)-1 Biomarker, IO biomarker, Immune cell: The R1441C-Lrrk2 mutation induces myeloid immune cell exhaustion in an age- and sex-dependent manner in mice. (Pubmed Central) - Nov 6, 2024
This phenotype was also observed in human peripheral myeloid cells, with monocyte-derived macrophages from patients with PD who had either the R1441C- or Y1699C-LRRK2 mutation exhibiting decreased pathogen uptake and increased PDL1 expression, consistent with immune cell exhaustion. Our findings that LRRK2 mutations conferred an immunological advantage at a young age but could predispose the carrier to age-acquired immune cell exhaustion have implications for the therapeutic development of LRRK2 inhibitors.
- |||||||||| Journal: Understanding Parkinson disease in Spain: Genetic and clinical insights. (Pubmed Central) - Nov 5, 2024
The observed genotype-phenotype correlations, along with sex-specific differences, emphasize the complexity of PD pathogenesis, underlining the importance of personalized approaches to PD diagnosis and treatment. Further investigations into genetic interactions and population-specific effects are warranted to enhance our understanding of PD etiology and improve patient care.
- |||||||||| Preclinical, Journal: Formation of templated inclusions in a forebrain ?-synuclein mouse model is independent of LRRK2. (Pubmed Central) - Nov 4, 2024
There was, however, a modest reduction in microglial activation induced by PFF delivery in the hippocampus of LRRK2 knockout mice, suggesting that LRRK2 may contribute to ?-synuclein-induced neuroinflammation. Collectively, our data indicate that the pathological accumulation of ?-synuclein in the mouse forebrain is largely independent of LRRK2.
- |||||||||| simvastatin / Generic mfg.
Journal, IO biomarker: A network-based systems genetics framework identifies pathobiology and drug repurposing in Parkinson's disease. (Pubmed Central) - Nov 1, 2024
Based on the network proximity-based drug repurposing followed by EHR data validation, we identified usage of simvastatin as being significantly associated with reduced incidence of PD (fall outcome: hazard ratio (HR) = 0.91, 95% confidence interval (CI): 0.87-0.94; for dementia outcome: HR = 0.88, 95% CI: 0.86-0.89), after adjusting for 267 covariates. Our network-based systems genetics framework identifies potential risk genes and repurposable drugs for PD and other neurodegenerative diseases if broadly applied.
- |||||||||| Undisclosed ATP13A2 modulator / Merck (MSD)
Journal: Parkinson's Disease Gene Screening in Familial Cases from Central and South America. (Pubmed Central) - Oct 19, 2024
There were substantial differences in the spectrum of variants observed in comparison to previous findings from PD families of European origin. Our data provide further evidence that differences exist between the genetic architecture of PD in Latinos and European-derived populations.
- |||||||||| Review, Journal: How Parkinson's Disease-Linked LRRK2 Mutations Affect Different CNS Cell Types. (Pubmed Central) - Oct 18, 2024
In this review, we will summarize recent and novel findings on the effects of PD-causing LRRK2 mutations in different nervous system cell types. This review will also provide novel insight into future areas of research at the intersection of LRRK2 cell biology, cell type specificity, and PD.
- |||||||||| MLi-2 / Merck (MSD)
Journal: Striatal cell-type-specific molecular signatures reveal therapeutic targets in a model of dystonia. (Pubmed Central) - Oct 17, 2024
We leveraged the unique molecular signatures of dSPNs and iSPNs in DRD mice to identify biochemical mechanisms that may be targets for therapeutics, including LRRK2 inhibition. Administration of the LRRK2 inhibitor MLi-2 ameliorated the dystonia in DRD mice suggesting a novel target for therapeutics and demonstrating that the delineation of cell-type-specific molecular signatures provides a powerful approach to revealing both CNS dysfunction and therapeutic targets in dystonia.
- |||||||||| Review, Journal: A Review on the Role of SNCA Gene in Neurodegenerative Diseases. (Pubmed Central) - Oct 16, 2024
Administration of the LRRK2 inhibitor MLi-2 ameliorated the dystonia in DRD mice suggesting a novel target for therapeutics and demonstrating that the delineation of cell-type-specific molecular signatures provides a powerful approach to revealing both CNS dysfunction and therapeutic targets in dystonia. Furthermore,
- |||||||||| Review, Journal: Hypoxia Pathways in Parkinson's Disease: From Pathogenesis to Therapeutic Targets. (Pubmed Central) - Oct 16, 2024
Additionally, the development of PD appears to be closely associated with hypoxia and hypoxic pathways. This review seeks to investigate the molecular interactions between hypoxia and PD, emphasizing the pathological role of hypoxic pathways in PD and exploring their potential as therapeutic targets.
- |||||||||| Journal: Natural variation in age-related dopamine neuron degeneration is glutathione dependent and linked to life span. (Pubmed Central) - Oct 10, 2024
Building on this, we find reduced expression of the Gcl catalytic subunit in both Drosophila strains vulnerable to age-related dopamine neuron loss and in the human brain from familial PD patients harboring the common LRRK2 G2019S mutation. Our study across Drosophila and human PD systems suggests that glutathione synthesis and levels play a conserved role in regulating age-related dopamine neuron health.
- |||||||||| Journal: The LRRK2 p.L1795F variant causes Parkinson's disease in the European population. (Pubmed Central) - Oct 7, 2024
Combined with published functional evidence showing strongly enhanced LRRK2 kinase activity, our findings provide conclusive evidence that the LRRK2 p.L1795F variant is pathogenic. It represents a rare cause of PD in the European population but needs to be included in genetic testing efforts and considered for ongoing gene-specific clinical trials.
- |||||||||| Quantitative Measurements of ?-Synuclein Seeds in Cerebrospinal Fluid Inform Diagnosis and Staging of Synucleinopathies () - Sep 27, 2024 - Abstract #MDSCongress2024MDS_Congress_2057;
Demonstrating high diagnostic efficacy, SAIA distinguished synucleinopathies (PD, multiple system atrophy, and dementia with Lewy bodies) from non-synucleinopathies and controls with sensitivities and specificities ranging between 80-100%, reflected by area under the curve values exceeding 0.9. Importantly, the assay revealed a positive correlation between CSF ?-syn seeds and disease severity, as measured by Unified Parkinson's Disease Rating Scale scores in PD patients.
- |||||||||| Journal: Parkinson's LRRK2-G2019S risk gene mutation drives sex-specific behavioral and cellular adaptations to chronic variable stress. (Pubmed Central) - Sep 27, 2024
The density of cFos-activated neurons across brain regions in both male and female Lrrk2 G2019S mice was generally lower compared to stressed Lrrk2 WT mice, except for the nucleus accumbens of male Lrrk2 G2019S mice, where cFos-labeled cell density was significantly higher than all other groups. Together, these data suggest that the Lrrk2 G2019S mutation differentially impacts anxiety-like behavioral responses to chronic stress in males and females that may reflect sex-specific adaptations observed in circuit activation patterns in some, but not all stress-related brain regions.
- |||||||||| Journal: Discovery and Optimization of N-Heteroaryl Indazole LRRK2 Inhibitors. (Pubmed Central) - Sep 26, 2024
Given these challenges, the team sought to leverage structure- and property-based drug design and expanded efflux transporter profiling to identify structurally distinct leads with enhanced CNS drug-likeness. Herein, we describe the discovery of a "reinvented" indazole series with improved physicochemical properties and efflux transporter profiles while maintaining excellent potency and off-target kinase selectivity, which resulted in advanced lead, compound 23.
- |||||||||| Preclinical, Journal: LRRK2G2019S Gene Mutation Causes Skeletal Muscle Impairment in Animal Model of Parkinson's Disease. (Pubmed Central) - Sep 23, 2024
Herein, we describe the discovery of a "reinvented" indazole series with improved physicochemical properties and efflux transporter profiles while maintaining excellent potency and off-target kinase selectivity, which resulted in advanced lead, compound 23. Taken together, these findings may provide new insights into the clinical and pathogenic involvement of LRRK2G2019 mutation in muscles, suggesting that the diseases may affect not only midbrain dopaminergic neurons, but also other tissues, and it may help overall clinical management of this devastating disease.
- |||||||||| Clinical, Review, Journal: Designing the First Trials for Parkinson's Prevention. (Pubmed Central) - Sep 21, 2024
Although these design strategies, along with the biological definition, subtype classification, and staging of the disease are evolving, all are driven by continued progress in the underlying science and integrated by a broad motivated community of stakeholders. While considerable methodological challenges remain, opportunities to move clinical trials of DMT to earlier points in the disease process than ever before have begun to unfold, and the prospects for PD prevention are nowtangible.
- |||||||||| Journal: New Pyrrolopyrimidines as LRRK2 Inhibitors for Treating Parkinson's Disease. (Pubmed Central) - Sep 20, 2024
This patent describes the novel pyrroloppyrimidine compounds as LRRK2 kinase inhibitors. The patent includes the synthesis of compounds, compositions containing them and their use in the treatment of or prevention of diseases associated with LRRK2 kinase activity, such as Parkinson's disease, Alzheimer's disease, and amyotrophic lateral sclerosis (ALS).
- |||||||||| ambroxol oral / Generic mfg., doxycycline / Generic mfg.
Journal: An Inducible Luminescent System to Explore Parkinson's Disease-Associated Genes. (Pubmed Central) - Sep 14, 2024
Moreover, the GCase chaperone ambroxol elicited an increase in the luminescence signal in HiBiT-tagged GBA1 cells, correlating with an increase in the levels of GCase in dopaminergic cells. Taken together, we have developed and validated a Doxycycline-inducible luminescence system to serve as a sensitive assay for the quantification, localization, and activity of HiBiT-tagged PD-associated proteins with reliable sensitivity and efficiency.
- |||||||||| Journal, Machine learning: Cluster Buster: A Machine Learning Algorithm for Genotyping SNPs from Raw Data. (Pubmed Central) - Sep 10, 2024
Cluster Buster's implementation significantly reduces manual labor for recovering no-call SNPs, refining genotype quality for the Global Parkinson's Genetics Program (GP2). This system facilitates better imputation and GWAS outcomes, ultimately contributing to a deeper understanding of genetic factors in NDDs.
- |||||||||| Review, Journal: Infectious Diseases. (Pubmed Central) - Sep 1, 2024
Finally, we describe roles for mixed lineage kinase 3 (MLK3) and leucine-rich repeat kinase (LRRK2) as key regulators of multiple inflammatory and apoptotic pathways important to the pathogenesis of PASC and HAND. Inhibition of these pathways provides a therapeutically synergistic method of treating both PASC and HAND.
- |||||||||| Review, Journal: Surgicogenomics: The Role of Genetics in Deep Brain Stimulation in Parkinson's Disease Patients. (Pubmed Central) - Aug 31, 2024
Emerging data also highlight the need to carefully consider the genetic background in the preoperative assessment of PD patients who are candidates for DBS, as genetic factors may affect the effectiveness of DBS in these patients. This review article discusses the role of genetics in DBS for PD patients, in an attempt to better understand inter-individual variability in DBS response, control of motor PD symptoms and appearance of non-motor symptoms, especially cognitive decline.
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