LRRK2 inhib 
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  • ||||||||||  The role of immune dysregulation of innate and adaptive immune cells in the prodromal and clinical stages of Parkinson (Exhibit (Pennsylvania Convention Center); In-Person) -  Jun 19, 2024 - Abstract #AAIC2024AAIC_2842;    
    If our hypothesis is correct, we expect that immune cell subsets from PD patients will display a signature of dysregulated immune response to stimulation. Furthermore, we expect that prodromal PD patients will exhibit dysregulated peripheral immune responses compared to controls, including altered mitochondrial and lysosomal function and cytokine release.
  • ||||||||||  Effects of Mediterranean vs. Western Diets on the Cerebral Cortical Pre-Synaptic Proteome in Nonhuman Primates. (Exhibit (Pennsylvania Convention Center); In-Person) -  Jun 19, 2024 - Abstract #AAIC2024AAIC_2630;    
    Together these observations demonstrate that diet composition drives temporal presynaptic protein composition, that transcription profiles strongly predict the presynaptic proteomic profile, and that presynaptic proteins are closely associated with peripheral metabolism, stress responsivity, and socioemotional behavior. These data demonstrate the impact of diet composition on brain molecular composition.
  • ||||||||||  haloperidol / Generic mfg.
    Journal:  LRRK2 mediates haloperidol-induced changes in indirect pathway striatal projection neurons. (Pubmed Central) -  Jun 19, 2024   
    demonstrate that haloperidol mediated changes in the striatal indirect pathway neurons and circuits are linked to Parkinson's disease associated LRRK2. Inhibiting LRRK2 kinase activity ameliorates the motoric side effects of haloperidol, suggesting a potential approach to alleviating the unwanted side effects of antipsychotics.
  • ||||||||||  Journal:  Parkinson's LRRK2-G2019S risk gene mutation drives sex-specific behavioral and cellular adaptations to chronic variable stress. (Pubmed Central) -  Jun 19, 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 stress-related brain regions.
  • ||||||||||  Journal:  In silico screening of LRRK2 WDR domain inhibitors using deep docking and free energy simulations. (Pubmed Central) -  Jun 14, 2024   
    Our results demonstrate the efficacy of the combined DD and ABFE approaches for hit identification for a target with no previously known hits. This approach is widely applicable for the efficient screening of ultra-large chemical libraries as well as rigorous protein-ligand binding affinity estimation leveraging modern computational resources.
  • ||||||||||  Journal:  Cell-autonomous role of leucine-rich repeat kinase in the protection of dopaminergic neuron survival. (Pubmed Central) -  Jun 10, 2024   
    Moreover, DA neurodegeneration is accompanied with increases in apoptosis and elevated microgliosis in the SNpc as well as decreases in DA terminals in the striatum, and is preceded by impaired motor coordination. Taken together, these findings provide the unequivocal evidence for the cell-intrinsic requirement of LRRK in DA neurons and raise the possibility that LRRK2 mutations may impair its protection of DA neurons, leading to DA neurodegeneration in PD.
  • ||||||||||  Duodopa (levodopa/carbidopa intraduodenal gel infusion) / AbbVie
    Journal:  p.L1795F LRRK2 variant is a common cause of Parkinson's disease in Central Europe. (Pubmed Central) -  Jun 10, 2024   
    Our data also suggest that p.L1795F may represent the most common currently known pathogenic LRRK2 variant in Central Europe compared to the more studied p.G2019S, being present in 1.81% of PD cases within the Central European cohort and 3.23% of familial PD cases. Together with the ongoing clinical trials for LRRK2 inhibitors, this finding emphasises the urgent need for more ethnic diversity in PD genetic research.
  • ||||||||||  PF-06447475 / Pfizer, SP600125 / BMS
    Journal:  Rotenone Induces a Neuropathological Phenotype in Cholinergic-like Neurons Resembling Parkinson's Disease Dementia (PDD). (Pubmed Central) -  Jun 6, 2024   
    Our observations highlight the importance of uncovering the function of the hLRRK2 orthologue dLrrk2 in D. melanogaster as an excellent model for pharmacological screenings. Interestingly, anti-oxidant and anti-amyloid cannabidiol (CBD), JNK inhibitor SP600125 (SP), TP53 inhibitor pifithrin- (PFT), and LRRK2 kinase inhibitor PF-06447475 (PF475) significantly diminish ROT-induced oxidative stress (OS), proteinaceous, and cell death markers in ChLNs compared to na
  • ||||||||||  Biomarker, Journal:  Left corticospinal tract could be a biomarker to identify the dual prodromal LRRK2/GBA mutated Parkinson's disease. (Pubmed Central) -  Jun 5, 2024   
    Interestingly, anti-oxidant and anti-amyloid cannabidiol (CBD), JNK inhibitor SP600125 (SP), TP53 inhibitor pifithrin- (PFT), and LRRK2 kinase inhibitor PF-06447475 (PF475) significantly diminish ROT-induced oxidative stress (OS), proteinaceous, and cell death markers in ChLNs compared to na L-CST, especially the 38th node, may potentially serve as a biomarker for distinguishing individuals with double mutation prodromal PD from the healthy population.
  • ||||||||||  Journal:  UNC-16 interacts with LRK-1 and WDFY-3 to regulate the termination of axon growth. (Pubmed Central) -  Jun 5, 2024   
    We also find that the axon termination defects caused by loss of UNC-16 function require the function of a genetic pathway that includes lrk-1 and wdfy-3, two genes that have been implicated in autophagy. These observations suggest a model where UNC-16 promotes axon termination by interacting with the endolysosomal system to regulate a pathway that includes LRK-1 and WDFY-3.
  • ||||||||||  Review, Journal:  Epigenetic Modifications in Parkinson's Disease: A Critical Review. (Pubmed Central) -  Jun 3, 2024   
    Epigenetic modifications play a significant role in the development of PD, with genes such as Parkin, PTEN-induced kinase 1 (PINK1), DJ1, Leucine-Rich Repeat Kinase 2 (LRRK2), and alpha-synuclein associated with the disease. The aberrant epigenetic changes implicated in the pathophysiology of PD and their impact on the design of novel therapeutic approaches are the primary focus of this review.
  • ||||||||||  MLi-2 / Merck (MSD)
    Journal:  LRRK2 kinase inhibition protects against Parkinson's disease-associated environmental toxicants. (Pubmed Central) -  May 18, 2024   
    We also found that cells with the LRRK2 G2019S mutation displayed exacerbated levels of toxicant induced ROS, but this was ameliorated by LRRK2 inhibition with MLi2. Collectively, these data support a role for LRRK2 in toxicant-induced mitochondrial dysfunction linked to PD risk through oxidative stress and the autophagic removal of damaged mitochondria.
  • ||||||||||  Journal:  Peripheral cutaneous synucleinopathy characteristics in genetic Parkinson's disease. (Pubmed Central) -  May 16, 2024   
    Cutaneous ?-synuclein SAA analysis of iPD and LRRK2 and GBA mutation patients revealed prion-like activity. P-?-syn deposition in peripheral cutaneous nerves, detected using SAA and immunofluorescence staining, may serve as an accurate biomarker for genetic PD and iPD in the future.
  • ||||||||||  Biomarker, Journal:  Prospective Role of PAK6 and 14-3-3? as Biomarkers for Parkinson's Disease. (Pubmed Central) -  Apr 26, 2024   
    amount in plasma represent a shared readout for patients affected by sporadic and LRRK2-linked Parkinson's disease. Overall, they can contribute to the establishment of an extended panel of biomarkers for the diagnosis of Parkinson's disease.
  • ||||||||||  Review, Journal:  Parkinson's Disease is Predominantly a (Pubmed Central) -  Apr 26, 2024   
    In addition, polygenic risk plays a considerable role in PD. However, it is likely that, in the majority of PD patients, a complex interplay of aging, genetic, environmental, and epigenetic factors leads to disease development.
  • ||||||||||  Review, Journal:  Perspectives of People At-Risk on Parkinson's Prevention Research. (Pubmed Central) -  Apr 26, 2024   
    Challenges and opportunities in the current environment include lack of awareness among primary care physicians and general neurologists about PD risk, legal and psychological implications of risk disclosure, limited return of individual research study results, and undefined engagement and integration of individuals at-risk into the broader Parkinson's community. Incorporating the perspectives of individuals at-risk as well as those living with PD at this early stage of prevention trial development is crucial to success.
  • ||||||||||  Journal:  LRRK2 G2019S impact on Parkinson disease; clinical phenotype and treatment in Tunisian patients. (Pubmed Central) -  Apr 23, 2024   
    Those with mutation exhibited an earlier age of onset(p=0.017),and female-PD cases had a higher mutation frequency (p=0.008).Mutation carriers displayed distinct clinical features,with a higher frequency of postural instability gait difficulty (PIGD)forms(adjusted-p<0.001).Throughout the disease progression,carriers showed a faster annual progression in UPDRS-III scores (adjusted-p=0.009) and a significantly higher Levodopa Equivalent Dosevalues in later stages(1060.81 vs. 877.83 for 6-8 years).Motor complications such as dyskinesia (adjusted-p<0.001) and motor fluctuations(31.9% vs. 25.7%,adjusted-p<0.001) were more prevalent in carriers,particularly in later stages.LRRK2-G2019S carriers also exhibited a lower prevalence of non-motor symptoms including cognitive disordersfor episodic memory(adjusted-p<0.001),attention(adjusted-p<0.001),and dysexecutive disorders (adjusted-p=0.039),as well asneuropsychiatric symptoms and dysautonomic signs. This study demonstrated the variability of clinical profile among Tunisian PD cases explained by the incomplete penetrance of LRRK2-G2019S that increases with age.Further studies with biomarker and disease progression data are necessary to improve PD management.
  • ||||||||||  Journal:  Micro-and mesoscale aspects of neurodegeneration in engineered human neural networks carrying the LRRK2 G2019S mutation. (Pubmed Central) -  Apr 22, 2024   
    The neurons carrying the LRRK2 G2019S mutation self-organized into networks with aberrant morphology and mitochondrial dynamics, affecting emerging structure-function relationships both at the micro-and mesoscale. Taken together, the findings of our study points toward an overall heightened metabolic demand in networks carrying the LRRK2 G2019S mutation, as well as a resilience to change in response to perturbation, compared to healthy isogenic controls.
  • ||||||||||  Journal:  LRRK2 G2019S Promotes Colon Cancer Potentially via LRRK2-GSDMD Axis-Mediated Gut Inflammation. (Pubmed Central) -  Apr 16, 2024   
    Notably, GSDMD inhibitors attenuate colitis in LRRK2 G2019S KI mice. Taken together, our findings offer experimental evidence indicating that the gain-of-kinase activity in LRRK2 promotes colorectal tumorigenesis, suggesting LRRK2 as a potential therapeutic target in colon cancer patients exhibiting hyper LRRK2 kinase activity.
  • ||||||||||  Biomarker, Journal:  Data-driven disease progression model of Parkinson's disease and effect of sex and genetic variants. (Pubmed Central) -  Apr 15, 2024   
    LRRK2 rs76904798 mutation also tended to delay disease progression by 10.4% but the difference was not significant. In conclusion, a long-term PD progression model was successfully constructed using SReFT from relatively short-term individual patient observations and depicted nonlinear changes in relevant biomarkers and their covariates, including sex and genetic variants.