LRRK2 Research Articles

LRRK2 is involved in heat exposure-induced acute lung injury and alveolar type II epithelial cell dysfunction

Heat exposure induces excessive hyperthermia associated with systemic inflammatory response that leads to multiple organ dysfunction including acute lung injury. However, how heat impairs the lung remains elusive so far. We aimed to explore the underlying mechanism by focusing on leucine-rich repeat kinase 2 (LRRK2), which was associated with lung homeostasis. Both in vivo and in vitro models were induced by heat exposure. Firstly, heat exposure exerted core temperature (Tc) disturbance, pulmonary dysfunction, atelectasis, inflammation, impaired energy metabolism, and reduced surfactant proteins in the lung of mice. In addition, decreased LRRK2 expression and increased heat shock proteins (HSPs) 70 were observed with heat exposure in both the lung of mice and alveolar type II epithelial cells (AT2). Furthermore, LRRK2 inhibition aggravated heat exposure-initiated Tc dysregulation, injury in the lung and AT2 cells, and enhanced HSP70 expression. In conclusion, LRRK2 is involved in heat-induced acute lung injury and AT2 cell dysfunction.

Neuroprotective Effects of the Nutraceutical Dehydrozingerone and Its C2-Symmetric Dimer in a Drosophila Model of Parkinson's Disease.

Parkinson's disease (PD) is a neurodegenerative disorder characterized by the loss of dopaminergic neurons responsible for unintended or uncontrollable movements. Mutations in the leucine-rich repeat kinase 2 locus contribute to genetic forms of PD. The fruit fly Drosophila melanogaster carrying this mutation (LRRK2-Dm) is an in vivo model of PD that develops motor impairment and stands for an eligible non-mammalian paradigm to test novel therapeutic approaches. Dehydrozingerone (DHZ) is a natural phenolic compound isolated from ginger and presents anti-inflammatory, antioxidant and neuroprotective properties, making it a potential therapeutic target for PD. We administered DHZ and its C2-symmetric dimer (DHZ-DIM) at 0.5 and 1 mM for 14 and 21 days in the LRRK2-Dm, with the aim of assessing changes in rescuing motor behavior, brain dopaminergic neurons, mitochondria and synapses (T-bars). The shorter treatment with both molecules revealed efficacy at the higher dose, improving climbing behavior with a prevention of dopaminergic neuronal demise. After 21 days, a recovery of the motor disability, dopaminergic neuron loss, mitochondrial damage and T-bars failure was observed with the DHZ-DIM. Our data indicate that the DHZ-DIM exerts a more potent neuroprotective effect with respect to the monomer in LRRK2-Dm, prompting further investigation of these compounds in rodent models of PD.

Multi-method computational evaluation of the inhibitors against leucine-rich repeat kinase 2 G2019S mutant for Parkinson's disease.

Leucine-rich repeat kinase 2 G2019S mutant (LRRK2 G2019S) is a potential target for Parkinson's disease therapy. In this work, the computational evaluation of the LRRK2 G2019S inhibitors was conducted via a combined approach which contains a preliminary screening of a large database of compounds via similarity and pharmacophore, a secondary selection via structure-based affinity prediction and molecular docking, and a rescoring treatment for the final selection. MD simulations and MM/GBSA calculations were performed to check the agreement between different prediction methods for these inhibitors. 331 experimental ligands were collected, and 170 were used to build the structure-activity relationship. Eight representative ligand structural models were employed in similarity searching and pharmacophore screening over 14 million compounds. The process for selecting proper molecular descriptors provides a successful sample which can be used as a general strategy in QSAR modelling. The rescoring used in this work presents an alternative useful treatment for ranking and selection.

Role of leucine-rich repeat kinase 2 in severe acute pancreatitis.

Intrapancreatic activation of trypsinogen caused by alcohol or high-fat intake and the subsequent autodigestion of the pancreas tissues by trypsin are indispensable events in the development of acute pancreatitis. In addition to this trypsin-centered paradigm, recent studies provide evidence that innate immune responses triggered by translocation of intestinal bacteria to the pancreas due to intestinal barrier dysfunction underlie the immunopathogenesis of acute pancreatitis. Although severe acute pancreatitis is often associated with pancreatic colonization by fungi, the molecular mechanisms linking fungus-induced immune responses to the development of severe acute pancreatitis are poorly understood. Leucine-rich repeat kinase 2 (LRRK2) is a multifunctional protein that mediates innate immune responses to fungi and bacteria. Mutations in Lrrk2 is a risk factor for Parkinson's disease and Crohn's disease, both of which are driven by innate immune responses to gut organisms. In this Minireview article, we discuss how activation of LRRK2 by the recognition of fungi induces severe acute pancreatitis.

Data-driven disease progression model of Parkinson's disease and effect of sex and genetic variants.

As Parkinson's disease (PD) progresses, there are multiple biomarker changes, and sex and genetic variants may influence the rate of progression. Data-driven, long-term disease progression model analysis may provide precise knowledge of the relationships between these risk factors and progression and would allow for the selection of appropriate diagnosis and treatment according to disease progression. To construct a long-term disease progression model of PD based on multiple biomarkers and evaluate the effects of sex and leucine-rich repeat kinase 2 (LRRK2) mutations, a technique derived from the nonlinear mixed-effects model (Statistical Restoration of Fragmented Time course [SReFT]) was applied to datasets of patients provided by the Parkinson's Progression Markers Initiative. Four biomarkers, including the Unified PD Rating Scale, were used, and a covariate analysis was performed to investigate the effects of sex and LRRK2-related mutations. A model of disease progression over ~30 years was successfully developed using patient data with a median of 6 years. Covariate analysis suggested that female sex and LRRK2 G2019S mutations were associated with 21.6% and 25.4% significantly slower progression, respectively. 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.

A Concise Enantioselective Synthesis of Fluorinated Pyrazolo-Piperidine GSK3901383A Enabled by an Organocatalytic Aza-Michael Addition.

A highly enantioselective organocatalytic aza-Michael addition of 4-nitro-pyrazole to ethyl (E)-2,2-difluoro-5-oxopent-3-enoate has been developed. This reaction enabled a concise, four-step, stereoselective synthesis of highly functionalized 3,3-difluoro-4-pyrazolo-piperidine GSK3901383A, a key intermediate for the synthesis of a leucine-rich repeat kinase 2 inhibitor API. Computational analysis provided insight into the steric requirements of the catalytic system, enabling rational selection of a highly selective catalyst.

Preclinical Evaluation of Novel Positron Emission Tomography (PET) Probes for Imaging Leucine-Rich Repeat Kinase 2 (LRRK2).

Parkinson's disease (PD) is one of the most highly debilitating neurodegenerative disorders, which affects millions of people worldwide, and leucine-rich repeat kinase 2 (LRRK2) mutations have been involved in the pathogenesis of PD. Developing a potent LRRK2 positron emission tomography (PET) tracer would allow for in vivo visualization of LRRK2 distribution and expression in PD patients. In this work, we present the facile synthesis of two potent and selective LRRK2 radioligands [11C]3 ([11C]PF-06447475) and [18F]4 ([18F]PF-06455943). Both radioligands exhibited favorable brain uptake and specific bindings in rodent autoradiography and PET imaging studies. More importantly, [18F]4 demonstrated significantly higher brain uptake in the transgenic LRRK2-G2019S mutant and lipopolysaccharide (LPS)-injected mouse models. This work may serve as a roadmap for the future design of potent LRRK2 PET tracers.

The LRRK2 kinase substrates RAB8a and RAB10 contribute complementary but distinct disease-relevant phenotypes in human neurons

Mutations in the LRRK2 gene cause familial Parkinson's disease presenting with pleomorphic neuropathology that can involve α-synuclein or tau accumulation. LRRK2 mutations are thought to converge upon a pathogenic increase in LRRK2 kinase activity. A subset of small RAB GTPases has been identified as LRRK2 substrates, with LRRK2-dependent phosphorylation resulting in RAB inactivation. We used CRISPR-Cas9 genome editing to generate a novel series of isogenic iPSC lines deficient in the two most well-validated LRRK2 substrates, RAB8a and RAB10, from deeply phenotyped healthy control lines. Thorough characterization of NGN2-induced neurons revealed opposing effects of RAB8a and RAB10 deficiency on lysosomal pH and Golgi organization, with isolated effects of RAB8a and RAB10 ablation on α-synuclein and tau, respectively. Our data demonstrate largely antagonistic effects of genetic RAB8a or RAB10 inactivation, which provide discrete insight into the pathologic features of their biochemical inactivation by pathogenic LRRK2 mutation in human disease.

Studies on the possible interplay between GBA1 and LRRK2 genes in Parkinson's disease using Drosophila models

Studies on the possible interplay between GBA1 and LRRK2 genes in Parkinson's disease using Drosophila models

Exploring the genetic factors behind the discrepancy in resistance to bovine tuberculosis between African zebu cattle and European taurine cattle

Caused by the pathogenic agent Mycobacterium bovis, bovine tuberculosis (bTB) is a major concern in cattle breeding due to both its zoonotic potential and economic impact. Greater resistance to this disease has been reported in certain African zebu breeds compared to European taurine breeds. However the genetic basis for the lower susceptibility to bTB infection observed in zebu cattle remains poorly explored. This study was conducted on whole genome sequencing data of three bTB infection-resistant African zebu breeds and two bTB infection-susceptible taurine breeds to decipher the genetic background. A set of four selection signature statistics based on linkage disequilibrium, site frequency spectrum, and population differentiation were used on SNPs whereas between population variance based VST and t-test were used on CNVs. As a complement, genes from previous literature reported as candidate genes for bTB resistance were also inspected to identify genetic variations. Interestingly, the resulting nine candidate genes had deleterious missense variants (SHC3, IFNGR1, TLR2, TLR6, IL1A, LRRK2, EP300 and IRAK4) or a CNV difference (CD48) segregating between the groups. The genes found in the study play a role in immune pathways activated during Mycobacterium infection, contributing to the proliferation of immune cells and the granuloma formation, ultimately modulating the outcome of the infectious event. In particular, a deleterious variant in the LRRK2 gene, whose deficiency has been linked to improved prognosis upon tuberculosis infection, was found in the bTB infection-resistant zebu breeds. Therefore, these genes constitute credible candidates in explaining the discrepancy in Mycobacterium bovis infection susceptibility among different breed.

The V-ATPase-ATG16L1 axis recruits LRRK2 to facilitate the lysosomal stress response.

Leucine-rich repeat kinase 2 (LRRK2), a Rab kinase associated with Parkinson's disease and several inflammatory diseases, has been shown to localize to stressed lysosomes and get activated to regulate lysosomal homeostasis. However, the mechanisms of LRRK2 recruitment and activation have not been well understood. Here, we found that the ATG8 conjugation system regulates the recruitment of LRRK2 as well as LC3 onto single membranes of stressed lysosomes/phagosomes. This recruitment did not require FIP200-containing autophagy initiation complex, nor did it occur on double-membrane autophagosomes, suggesting independence from canonical autophagy. Consistently, LRRK2 recruitment was regulated by the V-ATPase-ATG16L1 axis, which requires the WD40 domain of ATG16L1 and specifically mediates ATG8 lipidation on single membranes. This mechanism was also responsible for the lysosomal stress-induced activation of LRRK2 and the resultant regulation of lysosomal secretion and enlargement. These results indicate that the V-ATPase-ATG16L1 axis serves a novel non-autophagic role in the maintenance of lysosomal homeostasis by recruiting LRRK2.

The Effect of p.G2019S Mutation in the LRRK2 Gene on the Activity of Lysosomal Hydrolases and the Clinical Features of Parkinson's Disease Associated with p.N370S Mutation in the GBA1 Gene.

Mutations in the glucocerebrosidase (GBA1) and leucine-rich repeat kinase 2 (LRRK2) genes, encoding lysosomal enzyme glucocerebrosidase (GCase) and leucine-rich repeat kinase 2 (LRRK2), respectively, are the most common related to Parkinson's disease (PD). Recent data suggest a possible functional interaction between GCase and LRRK2 and their involvement in sphingolipid metabolism. The aim of the present study was to describe the clinical course and evaluate the lysosomal enzyme activities and sphingolipid concentrations in blood of patients with PD associated with dual mutations p.N370S GBA1 and p.G2019S LRRK2 (p.N370S/GBA-p.G2019S/LRRK2-PD) as well as in blood of asymptomatic mutation carriers (p.N370S/GBA1-p.G2019S/LRRK2-carrier). One patient with p.N370S/GBA1-p.G2019S/LRRK2-PD and one p.N370S/GBA1-p.G2019S/LRRK2-carrier were enrolled. GBA1-associated PD (GBA1-PD), LRRK2-associated PD (LRRK2-PD), sporadic PD (sPD) patients were described earlier by our research group. A neuropsychiatric examination of the p.N370S/GBA1-p.G2019S/LRRK2-PD patient was carried out using scales (Montreal Cognitive Assessment scale (MoCA), Mini-mental State Examination scale (MMSE), Frontal Assessment Batter scale (FAB), Hospital Anxiety, and Depression Scale (HADS), etc). Lysosomal enzyme activity (GCase, alpha-galactosidase [GLA], acid sphingomyelinase [ASMase], galactosylcerebrosidase [GALC]) and sphingolipid concentrations (hexasylsphingosine [HexSph], lysoglobotriaosylsphingosine [LysoGb3], lysosphingomyelin [LysoSM]) were assessed with high-performance liquid chromatography-tandem mass spectrometry in blood. The following comparison with the previously described groups of GBA1-PD and sPD patients were conducted. Clinical features of p.N370S/GBA1-p.G2019S/LRRK2-PD included an early age of onset of the disease (46 years) and mild cognitive and affective disorders (MMSE = 29, MoCA = 23), despite a long (24 years) course of the disease. Interestingly, no differences were found in hydrolase activity and lysosphingolipid concentrations between the p.N370S/GBA1-p.G2019S/LRRK2-PD patient and GBA1-PD patients. However, GCase activity was lower in these groups than in LRRK2-PD, sPD, and controls. Additionally, the p.N370S/GBA1-p.G2019S/LRRK2-PD patient was characterized by a pronounced decreased in ASMase activity and increased LysoSM concentration compared to the p.N370S/GBA1-p.G2019S/LRRK2-carrier (p = 0.023, p = 0.027, respectively). Based on one patient, our results indicate a protective effect of the p.G2019S mutation in the LRRK2 gene on clinical course of p.N370S/GBA1-PD. The identified pronounced alteration of ASMase activity and LysoSM concentration in p.N370S/GBA1-p.G2019S/LRRK2-PD provide the basis for the further research.

Manganese disrupts the maturation and degradation of axonal autophagosome leading to hippocampal synaptic toxicity in mice via the activation of LRRK2 on phosphorylation of Rab10

Manganese (Mn) overexposure induces hippocampal synaptotoxicity by the accumulation of dysfunctional synaptic vesicles (SVs). Leucine-rich repeat kinase 2 (LRRK2) kinase activity is involved in regulating axonal transport (autophagosomal maturation) and lysosomal function. Nevertheless, it remains unclear whether Mn-induced synaptotoxicity is associated with the LRRK2-mediated disruption of autophagosomal maturation in axonal transport and the impairment of lysosomes in hippocampal neurons. Here, we established models of manganism in C57BL/6 mice and hippocampal neuronal HT22 cells to verify the role of LRRK2-mediated Rab10 phosphorylation in the Mn-induced dysfunction of autophagy- lysosomal fusion. Our results proved that Mn-induced the disorder of axonal transport and that lysosome impairments were associated with the increased recruitment of phospho-Rab10 at the axon and lysosomes. Next, we established Lrrk2-KD and LRRK2 kinase- specific inhibitor (GNE-0877, GNE) pre-treated HT22 cells to inhibit Lrrk2 gene expression and kinase activity, respectively. In Mn-treated Lrrk2-KD or GNE-pretreated normal neurons, our results indicated that lysosomal pH and integrity and autophagic flow were restored, indicating by decreased levels of phospho-Rab10 on lysosomes and JNK-interacting proteins (JIP4). In addition, GNE pretreatment could provide protection against Mn-induced synaptotoxicity in vivo, which was evidenced by the partial recovery in synaptic plasticity and synaptic damage. Thus, the Mn-induced abnormal activation of LRRK2 affected lysosomes and the recruitment of phospho-Rab10 by JIP4, which disrupted autophagosomal maturation in proximal axons and resulted in the hippocampal synaptic toxicity of mice.

A potential patient stratification biomarker for Parkinson´s disease based on LRRK2 kinase-mediated centrosomal alterations in peripheral blood-derived cells

Parkinson´s disease (PD) is a common neurodegenerative movement disorder and leucine-rich repeat kinase 2 (LRRK2) is a promising therapeutic target for disease intervention. However, the ability to stratify patients who will benefit from such treatment modalities based on shared etiology is critical for the success of disease-modifying therapies. Ciliary and centrosomal alterations are commonly associated with pathogenic LRRK2 kinase activity and can be detected in many cell types. We previously found centrosomal deficits in immortalized lymphocytes from G2019S-LRRK2 PD patients. Here, to investigate whether such deficits may serve as a potential blood biomarker for PD which is susceptible to LRKK2 inhibitor treatment, we characterized patient-derived cells from distinct PD cohorts. We report centrosomal alterations in peripheral cells from a subset of early-stage idiopathic PD patients which is mitigated by LRRK2 kinase inhibition, supporting a role for aberrant LRRK2 activity in idiopathic PD. Centrosomal defects are detected in R1441G-LRRK2 and G2019S-LRRK2 PD patients and in non-manifesting LRRK2 mutation carriers, indicating that they accumulate prior to a clinical PD diagnosis. They are present in immortalized cells as well as in primary lymphocytes from peripheral blood. These findings indicate that analysis of centrosomal defects as a blood-based patient stratification biomarker may help nominate idiopathic PD patients who will benefit from LRRK2-related therapeutics.

Assessment of Mitochondrial Gene Activity in Dopaminergic Neuron Cultures Derived from Induced Pluripotent Stem Cells Obtained from Parkinson's Disease Patients

Introduction. Induced pluripotent stem cells (iPSCs) culturing allows modelling of neurodegenerative diseases in vitro and discovering its early biomarkers.
 Our objective was to evaluate the activity of genes involved in mitochondrial dynamics and functions in genetic forms of Parkinson's disease (PD) using cultures of dopaminergic neurons derived from iPSCs.
 Materials and methods. Dopaminergic neuron cultures were derived by reprogramming of the cells obtained from PD patients with SNCA and LRRK2 gene mutations, as well as from a healthy donor for control. Expression levels of 112 genes regulating mitochondrial structure, dynamics, and functions were assessed by multiplex gene expression profiling using NanoString nCounter custom mitochondrial gene expression panel.
 Results. When comparing the characteristics of the neurons from patients with genetic forms of PD to those of the control, we observed variations in the gene activity associated with the mitochondrial respiratory chain, the tricarboxylic acid cycle enzyme activities, biosynthesis of amino acids, oxidation of fatty acids, steroid metabolism, calcium homeostasis, and free radical quenching. Several genes in the cell cultures with SNCA and LRRK2 gene mutations exhibited differential expression. Moreover, these genes regulate mitophagy, mitochondrial DNA synthesis, redox reactions, cellular detoxification, apoptosis, as well as metabolism of proteins and nucleotides.
 Conclusions. The changes in gene network expression found in this pilot study confirm the role of disrupted mitochondrial homeostasis in the molecular pathogenesis of PD. These findings may contribute to the development of biomarkers and to the search for new therapeutic targets for the treatment of SNCA- and LRRK2-associated forms of the disease.

Identification of novel LRRK2 inhibitors by structure-based virtual screening and alchemical free energy calculation.

The Leucine-rich repeat kinase 2 (LRRK2) target has been identified as a promising drug target for Parkinson's disease (PD) treatment. This study focuses on optimizing the activity of LRRK2 inhibitors using alchemical relative binding free energy (RBFE) calculations. Initially, we assessed various free energy calculation methods across different LRRK2 kinase inhibitor scaffolds. The results indicate that alchemical free energy calculations are promising for prospective predictions on LRRK2 inhibitors, especially for the aminopyrimidine scaffold with an RMSE of 1.15 kcal mol-1 and Rp of 0.83. Following this, we optimized a potent LRRK2 kinase inhibitor identified from previous virtual screenings, featuring a novel scaffold. Guided by RBFE predictions using alchemical methods, this optimization led to the discovery of compound LY2023-001. This compound, with a [1,2,4]triazolo[5,6-b]indole scaffold, exhibited enhanced inhibitory activity against G2019S LRRK2 (IC50 = 12.9 nM). Molecular dynamics (MD) simulations revealed that LY2023-001 formed stable hydrogen bonds with Glu1948, and Ala1950 in the G2019S LRRK2 protein. Additionally, its phenyl substituents engage in strong electrostatic interactions with Lys1906 and van der Waals interactions with Leu1885, Phe1890, Val1893, Ile1933, Met1947, Leu1949, Leu2001, Ala2016, and Asp2017. Our findings underscore the potential of computational methods in the successful optimization of small molecules, offering important insights for the development of novel LRRK2 inhibitors.

Impairment of the trans-Golgi-Lysosomal Pathway Accelerates Dopaminergic Neuronal Senescence in LRRK2R1627P Rats.

Leucine-rich repeat kinase 2 (LRRK2)-R1628P mutation has been shown to be one of the common risk factors for Parkinson's disease (PD) in Asian populations, but the mechanism by which R1628P mutations cause neuronal dysfunction remains unknown. We used LRRK2R1627P knock-in rats (human LRRK2-R1628P corresponds to rat LRRK2-R1627P) to investigate the R1627P mutation on function of dopaminergic neurons (DANs) and their susceptibility to the environmental toxin Lipopolysaccharide (LPS) during aging. LRRK2R1627P rats showed no significant loss of DANs, dopamine and its metabolites, or motor dysfunction; however, spontaneous exploration and olfactory discrimination reduced, and dendritic spines of DANs showed degeneration. We found decreased pThr73-Rab10 located on the trans-Golgi, disrupted Golgi structure and lipofuscin accumulation in aged LRRK2R1627P rat DANs, and the protein related to trans-Golgi complex and regulating lysosome function were significantly reduced. Although the neuroinflammation of brain was not obvious in the aging process, we confirmed a decrease in the ratio of CD4+/CD8+ and B cells, an increase in inflammatory factors (TLR4, NFKB, TNF-α) in the periphery. Furthermore, we demonstrated that the R1627P mutation caused the abnormal accumulation of α-Syn in the aged rat intestine. LPS exacerbated pathological α-Syn aggregation in the small intestine of LRRK2 transgenic rats and spread to the brain via the gut-brain axis. This led to microgliosis in the substantia nigra, creating a pro-inflammatory environment and inducing DANs degeneration. Gut-brain axis disruption may be a key determinant of progression to R1628P-PD in R1628P carriers. This insight has important clinical implications and highlights the importance of monitoring and addressing gut-brain axis integrity in individuals with LRRK2 mutations.

In silico screening of LRRK2 WDR domain inhibitors using deep docking and free energy simulations.

The Critical Assessment of Computational Hit-Finding Experiments (CACHE) Challenge series is focused on identifying small molecule inhibitors of protein targets using computational methods. Each challenge contains two phases, hit-finding and follow-up optimization, each of which is followed by experimental validation of the computational predictions. For the CACHE Challenge #1, the Leucine-Rich Repeat Kinase 2 (LRRK2) WD40 Repeat (WDR) domain was selected as the target for in silico hit-finding and optimization. Mutations in LRRK2 are the most common genetic cause of the familial form of Parkinson's disease. The LRRK2 WDR domain is an understudied drug target with no known molecular inhibitors. Herein we detail the first phase of our winning submission to the CACHE Challenge #1. We developed a framework for the high-throughput structure-based virtual screening of a chemically diverse small molecule space. Hit identification was performed using the large-scale Deep Docking (DD) protocol followed by absolute binding free energy (ABFE) simulations. ABFEs were computed using an automated molecular dynamics (MD)-based thermodynamic integration (TI) approach. 4.1 billion ligands from Enamine REAL were screened with DD followed by ABFEs computed by MD TI for 793 ligands. 76 ligands were prioritized for experimental validation, with 59 compounds successfully synthesized and 5 compounds identified as hits, yielding a 8.5% hit rate. 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.

Multi-tracer PET correlation analysis reveals disease-specific patterns in Parkinson’s disease and asymptomatic LRRK2 pathogenic variant carriers compared to healthy controls

Several genetic pathogenic variants increase the risk of Parkinson’s disease (PD) with pathogenic variants in the leucine-rich repeat kinase 2 (LRRK2) gene being among the most common. A joint pattern analysis based on multi-set canonical correlation analysis (MCCA) was utilized to extract PD and LRRK2 pathogenic variant-specific spatial patterns in relation to healthy controls (HCs) from multi-tracer Positron Emission Tomography (PET) data. Spatial patterns were extracted for individual subject cohorts, as well as for pooled subject cohorts, to explore whether complementary spatial patterns of dopaminergic denervation are different in the asymptomatic and symptomatic stages of PD. The MCCA results are also compared to the traditional univariate analysis, which serves as a reference.We identified PD-induced spatial distribution alterations common to DAT and VMAT2 in both asymptomatic LRRK2 pathogenic variant carriers and PD subjects. The inclusion of HCs in the analysis demonstrated that the dominant common PD-induced pattern is related to an overall dopaminergic terminal density denervation, followed by asymmetry and rostro-caudal gradient with deficits in the less affected side still being the best marker of disease progression.The analysis was able to capture a trend towards PD-related patterns in the LRRK2 pathogenic variant carrier cohort with increasing age in line with the known increased risk of this patient cohort to develop PD as they age. The advantage of this method thus resides in its ability to identify not only regional differences in tracer binding between groups, but also common disease-related alterations in the spatial distribution patterns of tracer binding, thus potentially capturing more complex aspects of disease induced alterations.

Infectious Diseases.

Microglia, brain-resident innate immune cells, have been extensively studied in neurodegenerative contexts like Alzheimer's disease. The Coronavirus disease 2019 (COVID-19) pandemic highlighted how peripheral infection and inflammation can be detrimental to the neuroimmune milieu and initiate microgliosis driven by peripheral inflammation. Microglia can remain deleterious to brain health by sustaining inflammation in the central nervous system even after the clearance of the original immunogenic agents. In this chapter, we discuss how pulmonary infection with Severe Acute Respiratory Syndrome CoronaVirus 2 (SARS-CoV-2) can lead to neurovascular and neuroimmune inflammation causing the neurological syndrome of post-acute sequelae of COVID-19 (PASC). Further, we incorporate lessons from the Human Immunodeficiency Virus' (HIV's) effects on microglial functioning in the era of combined antiretroviral therapies (cART) that contribute to HIV-1 associated neurocognitive disorders (HAND). 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.