Vitamin B12 modulates Parkinson’s disease LRRK2 kinase activity through allosteric regulation and confers neuroprotection

Missense mutations in Leucine-Rich Repeat Kinase 2 (LRRK2) cause the majority of familial and some sporadic forms of Parkinson’s disease (PD). The hyperactivity of LRRK2 kinase induced by the pathogenic mutations underlies neurotoxicity, promoting the development of LRRK2 kinase inhibitors as therapeutics. Many potent and specific small molecule LRRK2 inhibitors have been reported with promise. However, nearly all inhibitors are ATP competitive – some with unwanted side effects and unclear clinical outcome - alternative types of LRRK2 inhibitors are lacking. Herein we find 5’-deoxyadenosylcobalamin (AdoCbl), a physiological form of the essential micronutrient vitamin B12 as a mixed-type allosteric inhibitor of LRRK2 kinase activity. Multiple assays show that AdoCbl directly binds LRRK2, leading to the alterations of protein conformation and ATP binding in LRRK2. STD-NMR analysis of a LRRK2 homologous kinase reveals the contact sites in AdoCbl that interface with the kinase domain. Furthermore, we provide evidence that AdoCbl modulates LRRK2 activity through disruption of LRRK2 dimerization. Treatment with AdoCbl inhibits LRRK2 kinase activity in cultured cells and brain tissue, and importantly prevents neurotoxicity in primary rodent cultures as well as in transgenic C. elegans and D. melanogaster expressing LRRK2 disease variants. Finally, AdoCbl alleviates deficits in dopamine release sustainability caused by LRRK2 disease variants in mouse models. Our study uncovers vitamin B12 as a novel class of LRRK2 kinase modulator with a distinct mechanism, which can be harnessed to develop new LRRK2-based PD therapeutics in the futur

Individual-specific functional connectivity improves prediction of Alzheimer’s disease’s symptoms in elderly people regardless of APOE ε4 genotype

Abstract To date, reliable biomarkers remain unclear that could link functional connectivity to patients’ symptoms for detecting and predicting the process from normal aging to Alzheimer’s disease (AD) in elderly people with specific genotypes. To address this, individual-specific functional connectivity is constructed for elderly participants with/without APOE ε4 allele. Then, we utilize recursive feature selection-based machine learning to reveal individual brain-behavior relationships and to predict the symptom transition in different genotypes. Our findings reveal that compared with conventional atlas-based functional connectivity, individual-specific functional connectivity exhibits higher classification and prediction performance from normal aging to AD in both APOE ε4 groups, while no significant performance is detected when the data of two genotyping groups are combined. Furthermore, individual-specific between-network connectivity constitutes a major contributor to assessing cognitive symptoms. This study highlights the essential role of individual variation in cortical functional anatomy and the integration of brain and behavior in predicting individualized symptoms

Pore-Scale Flow Fields of the Viscosity-Lost Partially Hydrolyzed Polyacrylamide Solution Caused by Sulfide Ion

The rheology of a partially hydrolyzed polyacrylamide (HPAM) solution plays an important role in its oil recovery during polymer flooding. However, multiple factors in brine, such as sulfide ions, cause a dramatic loss in the viscosity and oil recovery. To better understand the sulfide-induced viscosity loss and the consequent flow mechanisms in pore networks, the morphology of polymer solutions with and without sulfide ion was observed by scanning electron microscopy; and the variations of the pore scale flow fields were demonstrated by a microscopic visualization seepage experiment combined with Micro-PIV (Microscale Particle Image Velocimetry). The results showed that, with the presence of sulfide ion, the microstructure of the polymer changed from a uniform three-dimensional network structure to loose and uneven floccules, which resulted in viscosity loss (over 70% with 5-mg/L sulfide ion). Moreover, higher concentrations of sulfide ions (5 mg/L and 10 mg/L) resulted in earlier shear thinning characteristics than those with lower sulfide concentrations. Due to viscosity loss, the average flow velocity in the main stream of the microscopic seepage experiment increased more significantly than that without sulfide. However, the viscosity loss alone cannot independently explain the severe viscous fingering during the subsequent post-water flooding, which was about five times greater than that of the primary water flooding in terms of the velocity ratio between the mainstream and margin. A further pore-scale flow field analysis exhibited an eccentric and a bimodal velocity distribution in the throat along the radial and axial directions, respectively. The former distribution indicated that the adsorbed polymer on the pore wall was broken through by hydraulic shear due to the collapsed structure caused by sulfide ion. The latter suggested that another sulfide-induced impact was an earlier-occurring non-Newtonian characteristic with a low shear rate. Therefore, instead of viscosity loss, elastic loss is the dominant mechanism affecting the characteristics of the aggregate flow field under the action of sulfide. Microscopic flooding combined with Micro-PIV is a feasible and essential method to reveal pore scale flow mechanisms

Fluorescein Derivatives as Bifunctional Molecules for the Simultaneous Inhibiting and Labeling of FTO Protein

The FTO protein is unequivocally reported to play a critical role in human obesity and in the regulation of cellular levels of m⁶A modification, which makes FTO a significant and worthy subject of study. Here, we identified that fluorescein derivatives can selectively inhibit FTO demethylation, and the mechanisms behind these activities were elucidated after we determined the X-ray crystal structures of FTO/fluorescein and FTO/5-aminofluorescein. Furthermore, these inhibitors can also be applied to the direct labeling and enrichment of FTO protein combined with photoaffinity labeling assay