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Analysis of macroautophagy related proteins in G2019S LRRK2 Parkinson's disease brains with Lewy body pathology.

ABSTRACT: LRRK2, the gene encoding the multidomain kinase Leucine-Rich Repeat Kinase 2 (LRRK2), has been linked to familial and sporadic forms of Parkinson's disease (PD), as well as cancer, leprosy and Crohn's disease, establishing it as a target for discovery therapeutics. LRRK2 has been associated with a range of cellular processes, however its physiological and pathological functions remain unclear. The most prevalent LRRK2 mutations in PD have been shown to affect macroautophagy in various cellular models while a role in autophagy signalling has been recapitulated in vivo. Dysregulation of autophagy has been implicated in PD pathology, and this raises the possibility that differential autophagic activity is relevant to disease progression in PD patients carrying LRRK2 mutations. To examine the relevance of LRRK2 to the regulation of macroautophagy in a disease setting we examined the levels of autophagic markers in the basal ganglia of G2019S LRRK2 PD post-mortem tissue, in comparison to pathology-matched idiopathic PD (iPD), using immunoblotting (IB). Significantly lower levels of p62 and LAMP1 were observed in G2019S LRRK2 PD compared to iPD cases. Similarly, an increase in ULK1 was observed in iPD but was not reflected in G2019S LRRK2 PD cases. Furthermore, examination of p62 by immunohistochemistry (IH) recapitulated a distinct signature for G2019S PD. IH of LAMP1, LC3 and ULK1 broadly correlated with the IB results. Our data from a small but pathologically well-characterized cases highlights a divergence of G2019S PD carriers in terms of autophagic response in alpha-synuclein pathology affected brain regions compared to iPD.

SUBMITTER: Mamais A

PROVIDER: S-EPMC6361106 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Mutations in the gene encoding for leucine-rich repeat kinase 2 (LRRK2) are associated with both familial and sporadic Parkinson's disease (PD). LRRK2 encodes a large protein comprised of a GTPase and a kinase domain. All pathogenic variants converge on enhancing LRRK2 kinase substrate phosphorylation, and distinct LRRK2 kinase inhibitors are currently in various stages of clinical trials. Although the precise pathophysiological functions of LRRK2 remain largely unknown, PD-associated mutants have been shown to alter various intracellular vesicular trafficking pathways, especially those related to endolysosomal protein degradation events. In addition, biochemical studies have identified a subset of Rab proteins, small GTPases required for all vesicular trafficking steps, as substrate proteins for the LRRK2 kinase activity in vitro and in vivo. Therefore, it is crucial to evaluate the impact of such phosphorylation on neurodegenerative mechanisms underlying LRRK2-related PD, especially with respect to deregulated Rab-mediated endolysosomal membrane trafficking and protein degradation events. Surprisingly, a significant proportion of PD patients due to LRRK2 mutations display neuronal cell loss in the substantia nigra pars compacta in the absence of any apparent ?-synuclein-containing Lewy body neuropathology. These findings suggest that endolysosomal alterations mediated by pathogenic LRRK2 per se are not sufficient to cause ?-synuclein aggregation. Here, we will review current knowledge about the link between pathogenic LRRK2, Rab protein phosphorylation and endolysosomal trafficking alterations, and we will propose a testable working model whereby LRRK2-related PD may present with variable LB pathology.

| S-EPMC7287096 | biostudies-literature

Clinical correlations with Lewy body pathology in LRRK2-related Parkinson disease.

Project description:Mutations in leucine-rich repeat kinase 2 (LRRK2) are the most common cause of genetic Parkinson disease (PD) known to date. The clinical features of manifesting LRRK2 mutation carriers are generally indistinguishable from those of patients with sporadic PD. However, some PD cases associated with LRRK2 mutations lack Lewy bodies (LBs), a neuropathological hallmark of PD. We investigated whether the presence or absence of LBs correlates with different clinical features in LRRK2-related PD.We describe genetic, clinical, and neuropathological findings of 37 cases of LRRK2-related PD including 33 published and 4 unpublished cases through October 2013. Among the different mutations, the LRRK2 p.G2019S mutation was most frequently associated with LB pathology. Nonmotor features of cognitive impairment/dementia, anxiety, and orthostatic hypotension were correlated with the presence of LBs. In contrast, a primarily motor phenotype was associated with a lack of LBs.To our knowledge, this is the first report of clinicopathological correlations in a series of LRRK2-related PD cases. Findings from this selected group of patients with PD demonstrated that parkinsonian motor features can occur in the absence of LBs. However, LB pathology in LRRK2-related PD may be a marker for a broader parkinsonian symptom complex including cognitive impairment.

| S-EPMC4399368 | biostudies-literature

Dysregulated mRNA Translation in the G2019S LRRK2 and LRRK2 Knock-Out Mouse Brains.

Project description:The G2019S mutation in leucine-rich repeat kinase 2 (LRRK2) causes familial Parkinson's disease (PD) and is also found in a subset of idiopathic cases. Prior studies in Drosophila and human induced pluripotent stem cell (iPSC)-derived dopamine neurons uncovered a pronounced effect of G2019S LRRK2 on mRNA translation. It was previously reported that G2019S LRRK2 promotes translation of mRNAs with complex 5' untranslated region (UTR) secondary structure, resulting in increased expression of calcium channels and dysregulated calcium homeostasis in human dopamine neurons. Here, we show that dysregulated translation occurs in the brains of mammalian LRRK2 models in vivo Through ribosome profiling studies of global translation, we observe that mRNAs with complex 5'UTR structure are also preferentially translated in the G2019S LRRK2-expressing mouse brain. Reporter assays suggest that this 5'UTR preference is independent of translation initiation factors. Conversely, translation of mRNAs with complex 5'UTR secondary structure is downregulated in LRRK2 knock-out (KO) mouse brain, indicating a robust link between LRRK2 kinase activity and translation of mRNA with complex 5'UTR structure. Further, substantia nigra pars compacta (SNpc) dopamine neurons in the G2019S LRRK2-expressing brain exhibit increased calcium influx, which is consistent with the previous report from human dopamine neurons. These results collectively suggest that LRRK2 plays a mechanistic role in translational regulation, and the G2019S mutation in LRRK2 causes translational defects leading to calcium dysregulation in the mammalian brain.

| S-EPMC8638676 | biostudies-literature

Parkinson's disease susceptibility variants and severity of Lewy body pathology.

Project description:INTRODUCTION:Meta-analyses of genome-wide association studies (GWAS) have established common genetic risk factors for clinical Parkinson's disease (PD); however, associations between these risk factors and quantitative neuropathologic markers of disease severity have not been well-studied. This study evaluated associations of nominated variants from the most recent PD GWAS meta-analysis with Lewy body disease (LBD) subtype (brainstem, transitional, or diffuse) and pathologic burden of LB pathology as measured by LB counts in five cortical regions in a series of LBD cases. METHODS:547 autopsy-confirmed cases of LBD were included and genotyped for 29 different GWAS-nominated PD risk variants. LB counts were measured in middle frontal (MF), superior temporal (ST), inferior parietal (IP), cingulate (CG), and parahippocampal (PH) gyri. RESULTS:None of the variants examined were significantly associated with LB counts in any brain region or with LBD subtype after correcting for multiple testing. Nominally significant (P < 0.05) associations with LB counts where the direction of association was in agreement with that observed in the PD GWAS meta-analysis were observed for variants in BCKDK/STX1B (MF, ST, IP) and SNCA (ST). Additionally, MIR4697 and BCKDK/STX1B variants were nominally associated with LBD subtype. CONCLUSION:The lack of a significant association between PD GWAS variants and severity of LB pathology is consistent with the generally subtle association odds ratios that have been observed in disease-risk analysis. These results also suggest that genetic factors other than the susceptibility loci may determine quantitative neuropathologic outcomes in patients with LBD.

| S-EPMC5716921 | biostudies-literature

Pharmacological rescue of impaired mitophagy in Parkinson's disease-related LRRK2 G2019S knock-in mice.

Project description:Parkinson's disease (PD) is a major and progressive neurodegenerative disorder, yet the biological mechanisms involved in its aetiology are poorly understood. Evidence links this disorder with mitochondrial dysfunction and/or impaired lysosomal degradation - key features of the autophagy of mitochondria, known as mitophagy. Here, we investigated the role of LRRK2, a protein kinase frequently mutated in PD, in this process in vivo. Using mitophagy and autophagy reporter mice, bearing either knockout of LRRK2 or expressing the pathogenic kinase-activating G2019S LRRK2 mutation, we found that basal mitophagy was specifically altered in clinically relevant cells and tissues. Our data show that basal mitophagy inversely correlates with LRRK2 kinase activity in vivo. In support of this, use of distinct LRRK2 kinase inhibitors in cells increased basal mitophagy, and a CNS penetrant LRRK2 kinase inhibitor, GSK3357679A, rescued the mitophagy defects observed in LRRK2 G2019S mice. This study provides the first in vivo evidence that pathogenic LRRK2 directly impairs basal mitophagy, a process with strong links to idiopathic Parkinson's disease, and demonstrates that pharmacological inhibition of LRRK2 is a rational mitophagy-rescue approach and potential PD therapy.

| S-EPMC8331189 | biostudies-literature

Overexpression of Parkinson's Disease-Associated Mutation LRRK2 G2019S in Mouse Forebrain Induces Behavioral Deficits and α-Synuclein Pathology.

Project description:Mutations in the leucine-rich repeat kinase 2 (LRRK2) gene have been identified as an unambiguous cause of late-onset, autosomal-dominant familial Parkinson's disease (PD) and LRRK2 mutations are the strongest genetic risk factor for sporadic PD known to date. A number of transgenic mice expressing wild-type or mutant LRRK2 have been described with varying degrees of LRRK2-related abnormalities and modest pathologies. None of these studies directly addressed the role of the kinase domain in the changes observed and none of the mice present with robust features of the human disease. In an attempt to address these issues, we created a conditional LRRK2 G2019S (LRRK2 GS) mutant and a functionally negative control, LRRK2 G2019S/D1994A (LRRK2 GS/DA). Expression of LRRK2 GS or LRRK2 GS/DA was conditionally controlled using the tet-off system in which the presence of tetracycline-transactivator protein (tTA) with a CAMKIIα promoter (CAMKIIα-tTA) induced expression of TetP-LRRK2 GS or TetP-LRRK2 GS/DA in the mouse forebrain. Overexpression of LRRK2 GS in mouse forebrain induced behavioral deficits and α-synuclein pathology in a kinase-dependent manner. Similar to other genetically engineered LRRK2 GS mice, there was no significant loss of dopaminergic neurons. These mice provide an important new tool to study neurobiological changes associated with the increased kinase activity from the LRRK2 G2019S mutation, which may ultimately lead to a better understanding of not only the physiologic actions of LRRK2, but also potential pathologic actions that underlie LRRK2 GS-associated PD.

| S-EPMC5355896 | biostudies-literature

The genetic contributions of SNCA and LRRK2 genes to Lewy Body pathology in Alzheimer's disease.

Project description:The molecular genetic basis that leads to Lewy Body (LB) pathology in 15-20% of Alzheimer disease cases (LBV/AD) was largely unknown. Alpha-synuclein (SNCA) and Leucine-rich repeat kinase2 (LRRK2) have been implicated in the pathogenesis of Parkinson's disease (PD), the prototype of LB spectrum disorders. We tested the association of SNCA variants with LB pathology in AD. We then stratified the SNCA association analyses by LRRK2 genotype. We also investigated the expression regulation of SNCA and LRRK2 in relation to LB pathology. We evaluated the differences in SNCA-mRNA and LRRK2-mRNA levels as a function of LB pathology in the temporal cortex (TC) from autopsy-confirmed LBV/AD cases and AD controls. We further investigated the cis-effect of the LB pathology-associated genetic variants within the SNCA and LRRK2 loci on the mRNA expression of these genes. SNCA SNPs rs3857059 and rs2583988 showed significant associations with increased risk for LB pathology. When the analyses were stratified by LRRK2-rs1491923 genotype, the associations became stronger for both SNPs and an association was also observed with rs2619363. Expression analysis demonstrated that SNCA- and LRRK2-mRNA levels were significantly higher in TC from LBV/AD brains compared with AD controls. Furthermore, SNCA-mRNA expression level in the TC was associated with rs3857059; homozygotes for the minor allele showed significant higher expression. LRRK2-transcript levels were increased in carriers of rs1491923 minor allele. Our findings demonstrated that SNCA contributes to LB pathology in AD patients, possibly via interaction with LRRK2, and suggested that expression regulation of these genes may be the molecular basis underlying the observed LB associations.

| S-EPMC4140463 | biostudies-literature

Modeling G2019S-LRRK2 Sporadic Parkinson's Disease in 3D Midbrain Organoids.

Project description:Recent advances in generating three-dimensional (3D) organoid systems from stem cells offer new possibilities for disease modeling and drug screening because organoids can recapitulate aspects of in vivo architecture and physiology. In this study, we generate isogenic 3D midbrain organoids with or without a Parkinson's disease-associated LRRK2 G2019S mutation to study the pathogenic mechanisms associated with LRRK2 mutation. We demonstrate that these organoids can recapitulate the 3D pathological hallmarks observed in patients with LRRK2-associated sporadic Parkinson's disease. Importantly, analysis of the protein-protein interaction network in mutant organoids revealed that TXNIP, a thiol-oxidoreductase, is functionally important in the development of LRRK2-associated Parkinson's disease in a 3D environment. These results provide proof of principle for the utility of 3D organoid-based modeling of sporadic Parkinson's disease in advancing therapeutic discovery.

| S-EPMC6410341 | biostudies-literature

The Parkinson's disease associated mutation LRRK2-G2019S affects astrocyte specification

Project description:We report the altered transcriptomic profile of astrocytes in midbrain organoids differentiated for 35 and 70 days and generated from a stem cell line carrying the LRRK2-G2019S mutation compared to the isogenic pair.

2020-05-01 | GSE133894 | GEO

Lewy body-like ?-synuclein aggregates resist degradation and impair macroautophagy.

Project description:Cytoplasmic ?-synuclein (?-syn) aggregates, referred to as Lewy bodies, are pathological hallmarks of a number of neurodegenerative diseases, most notably Parkinson disease. Activation of macroautophagy is suggested to facilitate degradation of certain proteinaceous inclusions, but it is unclear if this pathway is capable of degrading ?-syn aggregates. Here, we examined this issue by utilizing cellular models in which intracellular Lewy body-like ?-syn inclusions accumulate after internalization of pre-formed ?-syn fibrils into ?-syn-expressing HEK293 cells or cultured primary neurons. We demonstrate that ?-syn inclusions cannot be effectively degraded, even though they co-localize with essential components of both the autophagic and proteasomal protein degradation pathways. The ?-syn aggregates persist even after soluble ?-syn levels have been substantially reduced, suggesting that once formed, the ?-syn inclusions are refractory to clearance. Importantly, we also find that ?-syn aggregates impair overall macroautophagy by reducing autophagosome clearance, which may contribute to the increased cell death that is observed in aggregate-bearing cells.

| S-EPMC3663539 | biostudies-literature

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