scholarly journals Robust kinase- and age-dependent dopaminergic and norepinephrine neurodegeneration in LRRK2 G2019S transgenic mice

2018 ◽  
Vol 115 (7) ◽  
pp. 1635-1640 ◽  
Author(s):  
Yulan Xiong ◽  
Stewart Neifert ◽  
Senthilkumar S. Karuppagounder ◽  
Qinfang Liu ◽  
Jeannette N. Stankowski ◽  
...  
Keyword(s):  
Transgenic Mice ◽  
Molecular Mechanisms ◽  
Model Development ◽  
Behavioral Deficits ◽  
Lrrk2 G2019s ◽  
Age Dependent ◽  
Dependent Cell ◽  
A Cell ◽  
Mutant Lrrk2 ◽  
Familial Parkinson’S Disease

Mutations in LRRK2 are known to be the most common genetic cause of sporadic and familial Parkinson’s disease (PD). Multiple lines of LRRK2 transgenic or knockin mice have been developed, yet none exhibit substantial dopamine (DA)-neuron degeneration. Here we develop human tyrosine hydroxylase (TH) promoter-controlled tetracycline-sensitive LRRK2 G2019S (GS) and LRRK2 G2019S kinase-dead (GS/DA) transgenic mice and show that LRRK2 GS expression leads to an age- and kinase-dependent cell-autonomous neurodegeneration of DA and norepinephrine (NE) neurons. Accompanying the loss of DA neurons are DA-dependent behavioral deficits and α-synuclein pathology that are also LRRK2 GS kinase-dependent. Transmission EM reveals that that there is an LRRK2 GS kinase-dependent significant reduction in synaptic vesicle number and a greater abundance of clathrin-coated vesicles in DA neurons. These transgenic mice indicate that LRRK2-induced DA and NE neurodegeneration is kinase-dependent and can occur in a cell-autonomous manner. Moreover, these mice provide a substantial advance in animal model development for LRRK2-associated PD and an important platform to investigate molecular mechanisms for how DA neurons degenerate as a result of expression of mutant LRRK2.

scholarly journals Mitochondrial clearance and maturation of autophagosomes are compromised in LRRK2 G2019S familial Parkinson’s disease patient fibroblasts

2019 ◽  
Vol 28 (19) ◽  
pp. 3232-3243 ◽  
Author(s):  
Joanna A Korecka ◽  
Ria Thomas ◽  
Dan P Christensen ◽  
Anthony J Hinrich ◽  
Eliza J Ferrari ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Human Fibroblasts ◽  
Disease Patient ◽  
G2019s Mutation ◽  
Mechanistic Analysis ◽  
Lrrk2 G2019s ◽  
Diagnostic Approaches ◽  
Mutant Lrrk2 ◽  
Familial Parkinson’S Disease

AbstractThis study utilized human fibroblasts as a preclinical discovery and diagnostic platform for identification of cell biological signatures specific for the LRRK2 G2019S mutation producing Parkinson’s disease (PD). Using live cell imaging with a pH-sensitive Rosella biosensor probe reflecting lysosomal breakdown of mitochondria, mitophagy rates were found to be decreased in fibroblasts carrying the LRRK2 G2019S mutation compared to cells isolated from healthy subject (HS) controls. The mutant LRRK2 increased kinase activity was reduced by pharmacological inhibition and targeted antisense oligonucleotide treatment, which normalized mitophagy rates in the G2019S cells and also increased mitophagy levels in HS cells. Detailed mechanistic analysis showed a reduction of mature autophagosomes in LRRK2 G2019S fibroblasts, which was rescued by LRRK2 specific kinase inhibition. These findings demonstrate an important role for LRRK2 protein in regulation of mitochondrial clearance by the lysosomes, which is hampered in PD with the G2019S mutation. The current results are relevant for cell phenotypic diagnostic approaches and potentially for stratification of PD patients for targeted therapy.

scholarly journals Loss of the common immune coreceptor BAK1 leads to NLR-dependent cell death

2020 ◽  
Vol 117 (43) ◽  
pp. 27044-27053 ◽  
Author(s):  
Yujun Wu ◽  
Yang Gao ◽  
Yanyan Zhan ◽  
Hong Kui ◽  
Hongyan Liu ◽  
...  
Keyword(s):  
Cell Death ◽  
Pseudomonas Syringae ◽  
Molecular Mechanisms ◽  
Receptor Protein ◽  
Dependent Manner ◽  
Effector Triggered Immunity ◽  
Dependent Cell ◽  
A Cell ◽  
Cell Death Phenotype ◽  
Recognition Receptor

Plants utilize a two-tiered immune system consisting of pattern recognition receptor (PRR)-triggered immunity (PTI) and effector-triggered immunity (ETI) to defend themselves against pathogenic microbes. The receptor protein kinase BAK1 plays a central role in multiple PTI signaling pathways in Arabidopsis. However, double mutants made by BAK1 and its closest paralog BKK1 exhibit autoimmune phenotypes, including cell death resembling a typical nucleotide-binding leucine-rich repeat protein (NLR)-mediated ETI response. The molecular mechanisms of the cell death caused by the depletion of BAK1 and BKK1 are poorly understood. Here, we show that the cell-death phenotype of bak1 bkk1 is suppressed when a group of NLRs, ADR1s, are mutated, indicating the cell-death of bak1 bkk1 is the consequence of NLR activation. Furthermore, introduction of a Pseudomonas syringae effector HopB1, which proteolytically cleaves activated BAK1 and its paralogs via either gene transformation or bacterium-delivery, results in a cell-death phenotype in an ADR1s-dependent manner. Our study thus pinpoints that BAK1 and its paralogs are likely guarded by NLRs.

scholarly journals The E3 ligase TRIM1 ubiquitinates LRRK2 and controls its localization, degradation, and toxicity

2020 ◽  
Author(s):  
Adrienne E. D. Stormo ◽  
Molly FitzGibbon ◽  
Farbod Shavarebi ◽  
Elizabeth M. Earley ◽  
Lotus S. Lum ◽  
...  
Keyword(s):  
Ubiquitin Ligase ◽  
Kinase Activity ◽  
Missense Mutations ◽  
Quantitative Mass Spectrometry ◽  
Lrrk2 G2019s ◽  
Mutant Lrrk2 ◽  
Lrrk2 Kinase ◽  
Regulatory Loop ◽  
Familial Parkinson’S Disease ◽  
Lrrk2 Kinase Activity

AbstractMissense mutations in leucine-rich repeat kinase 2 (LRRK2) are the most common cause of familial Parkinson’s Disease (PD); however, pathways regulating LRRK2 subcellular localization, function, and turnover are not fully defined. We performed quantitative mass spectrometry-based interactome studies to identify 48 novel LRRK2 interactors, including the microtubule-associated E3 ubiquitin ligase TRIM1 (Tripartite Motif Family 1). TRIM1 recruits LRRK2 to the microtubule cytoskeleton for ubiquitination and proteasomal degradation by binding LRRK2822-982, a flexible interdomain region we designate the “Regulatory Loop” (RL). Phosphorylation of LRRK2 Ser910/935 within LRRK2 RL serves as a molecular switch controlling LRRK2’s association with cytoplasmic 14-3-3 versus microtubule-bound TRIM1. Association with TRIM1 prevents upregulation of LRRK2 kinase activity by Rab29 and also rescues neurite outgrowth deficits caused by PD-driving mutant LRRK2 G2019S. Our data suggest that TRIM1 is a critical regulator of LRRK2, modulating its cytoskeletal recruitment, turnover, kinase activity, and cytotoxicity.

Stroke-induced opposite and age-dependent changes of vessel-associated markers in co-morbid transgenic mice with Alzheimer-like alterations

2013 ◽  
Vol 250 ◽  
pp. 270-281 ◽  
Author(s):  
Cheryl A. Hawkes ◽  
Dominik Michalski ◽  
Rebecca Anders ◽  
Sabine Nissel ◽  
Jens Grosche ◽  
...  
Keyword(s):  
Transgenic Mice ◽  
Age Dependent

scholarly journals Clinical and Biological Characteristics of Medullary and Extramedullary Plasma Cell Dyscrasias

Biology ◽  
2021 ◽  
Vol 10 (7) ◽  
pp. 629
Author(s):  
Snjezana Janjetovic ◽  
Philipp Lohneis ◽  
Axel Nogai ◽  
Derya Balci ◽  
Leo Rasche ◽  
...  
Keyword(s):  
Plasma Cell ◽  
Molecular Mechanisms ◽  
Biological Characteristics ◽  
Surface Glycoprotein ◽  
Cell Surface Glycoprotein ◽  
Similar Frequency ◽  
Cytogenetic Aberrations ◽  
A Cell ◽  
Plasma Cell Dyscrasias ◽  
Extramedullary Plasmocytoma

Background: Extramedullary plasma cell (PC) disorders may occur as extramedullary disease in multiple myeloma (MM-EMD) or as primary extramedullary plasmocytoma (pEMP)/solitary osseous plasmocytoma (SOP). In this study, we aimed to obtain insights into the molecular mechanisms of extramedullary spread of clonal PC. Methods: Clinical and biological characteristics of 87 patients with MM-EMD (n = 49), pEMP/SOP (n = 20) and classical MM (n = 18) were analyzed by using immunohistochemistry (CXCR4, CD31, CD44 and CD81 staining) and cytoplasmic immunoglobulin staining combined with fluorescence in situ hybridization (cIg-FISH). Results: High expression of CD44, a cell-surface glycoprotein involved in cell-cell interactions, was significantly enriched in MM-EMD (90%) vs. pEMP/SOP (27%) or classical MM (33%) (p < 0.001). In addition, 1q21 amplification by clonal PC occurred at a similar frequency of MM-EMD (33%), pEMP/SOP (57%) and classical MM (44%). Conversely, del(17p13), t(4;14) and t(14;16) were completely absent in pEMP/SOP. Besides this, 1q21 amplification was identified in 64% of not paraskeletal samples from MM-EMD or pEMP compared to 9% of SOP or paraskeletal MM-EMD/pEMP and 44% of classical MM samples, respectively (p = 0.02). Conclusion: Expression of molecules involved in homing and cytogenetic aberrations differ between MM with or without EMD and pEMP/SOP.

scholarly journals Early alterations of neurovascular unit in the retina in mouse models of tauopathy

2021 ◽  
Vol 9 (1) ◽  
Author(s):  
Fan Xia ◽  
Yonju Ha ◽  
Shuizhen Shi ◽  
Yi Li ◽  
Shengguo Li ◽  
...  
Keyword(s):  
Transgenic Mice ◽  
Mouse Models ◽  
Molecular Mechanisms ◽  
Early Stage ◽  
Leukocyte Adhesion ◽  
Neurovascular Unit ◽  
Integrated Analysis ◽  
Therapeutic Effects ◽  
Retinal Ganglion ◽  
Potential Biomarker

AbstractThe retina, as the only visually accessible tissue in the central nervous system, has attracted significant attention for evaluating it as a biomarker for neurodegenerative diseases. Yet, most of studies focus on characterizing the loss of retinal ganglion cells (RGCs) and degeneration of their axons. There is no integrated analysis addressing temporal alterations of different retinal cells in the neurovascular unit (NVU) in particular retinal vessels. Here we assessed NVU changes in two mouse models of tauopathy, P301S and P301L transgenic mice overexpressing the human tau mutated gene, and evaluated the therapeutic effects of a tau oligomer monoclonal antibody (TOMA). We found that retinal edema and breakdown of blood–retina barrier were observed at the very early stage of tauopathy. Leukocyte adhesion/infiltration, and microglial recruitment/activation were constantly increased in the retinal ganglion cell layer of tau transgenic mice at different ages, while Müller cell gliosis was only detected in relatively older tau mice. Concomitantly, the number and function of RGCs progressively decreased during aging although they were not considerably altered in the very early stage of tauopathy. Moreover, intrinsically photosensitive RGCs appeared more sensitive to tauopathy. Remarkably, TOMA treatment in young tau transgenic mice significantly attenuated vascular leakage, inflammation and RGC loss. Our data provide compelling evidence that abnormal tau accumulation can lead to pathology in the retinal NVU, and vascular alterations occur more manifest and earlier than neurodegeneration in the retina. Oligomeric tau-targeted immunotherapy has the potential to treat tau-induced retinopathies. These data suggest that retinal NVU may serve as a potential biomarker for diagnosis and staging of tauopathy as well as a platform to study the molecular mechanisms of neurodegeneration.

scholarly journals Polymodal Functionality of C. elegans OLL Neurons in Mechanosensation and Thermosensation

2021 ◽  
Author(s):  
Yuedan Fan ◽  
Wenjuan Zou ◽  
Jia Liu ◽  
Umar Al-Sheikh ◽  
Hankui Cheng ◽  
...  
Keyword(s):  
Glutamate Receptor ◽  
Sensory Neurons ◽  
Molecular Mechanisms ◽  
Temperature Sensitive ◽  
Cold Sensation ◽  
Cold Response ◽  
C Elegans ◽  
Sensory Modalities ◽  
A Cell ◽  
Bona Fide

AbstractSensory modalities are important for survival but the molecular mechanisms remain challenging due to the polymodal functionality of sensory neurons. Here, we report the C. elegans outer labial lateral (OLL) sensilla sensory neurons respond to touch and cold. Mechanosensation of OLL neurons resulted in cell-autonomous mechanically-evoked Ca2+ transients and rapidly-adapting mechanoreceptor currents with a very short latency. Mechanotransduction of OLL neurons might be carried by a novel Na+ conductance channel, which is insensitive to amiloride. The bona fide mechano-gated Na+-selective degenerin/epithelial Na+ channels, TRP-4, TMC, and Piezo proteins are not involved in this mechanosensation. Interestingly, OLL neurons also mediated cold but not warm responses in a cell-autonomous manner. We further showed that the cold response of OLL neurons is not mediated by the cold receptor TRPA-1 or the temperature-sensitive glutamate receptor GLR-3. Thus, we propose the polymodal functionality of OLL neurons in mechanosensation and cold sensation.

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