scholarly journals Caught in the act: LRRK2 in exosomes

2019 ◽  
Vol 47 (2) ◽  
pp. 663-670 ◽  
Author(s):  
Shijie Wang ◽  
Andrew B. West
Keyword(s):  
Extracellular Space ◽  
Late Onset ◽  
Leucine Rich Repeat ◽  
Therapeutic Approaches ◽  
Post Translational Modifications ◽  
Extracellular Milieu ◽  
Late Endosomes ◽  
Lrrk2 Gene ◽  
Different Types ◽  
Lrrk2 Protein

Abstract Mutations in the leucine-rich repeat kinase 2 (LRRK2) gene are a frequent genetic cause of late-onset Parkinson's disease (PD) and a target for therapeutic approaches. LRRK2 protein can influence vesicle trafficking events in the cytosol, with action both in endosomal and lysosomal pathways in different types of cells. A subset of late endosomes harbor intraluminal vesicles that can be secreted into the extracellular milieu. These extracellular vesicles, called exosomes, package LRRK2 protein for transport outside the cell into easily accessed biofluids. Both the cytoplasmic complement of LRRK2 as well as the exosome-associated fraction of protein appears regulated in part by interactions with 14-3-3 proteins. LRRK2 inside exosomes have disease-linked post-translational modifications and are relatively stable compared with unprotected proteins in the extracellular space or disrupted cytosolic compartments. Herein, we review the biology of exosome-associated LRRK2 and the potential for utility in diagnosis, prognosis, and theragnosis in PD and other LRRK2-linked diseases.

scholarly journals Models for LRRK2-Linked Parkinsonism

2011 ◽  
Vol 2011 ◽  
pp. 1-16 ◽  
Author(s):  
Tianxia Li ◽  
DeJun Yang ◽  
Sarah Sushchky ◽  
Zhaohui Liu ◽  
Wanli W. Smith
Keyword(s):  
Dopaminergic Neurons ◽  
Autosomal Dominant ◽  
Dopaminergic System ◽  
Late Onset ◽  
Lewy Bodies ◽  
Leucine Rich Repeat ◽  
Protein Deposition ◽  
Lrrk2 Gene ◽  
The Brain ◽  
Potential Therapeutics

Parkinson's disease (PD) is a progressive neurodegenerative movement disorder characterized by the selective loss of dopaminergic neurons and the presence of Lewy bodies. The pathogenesis of PD is not fully understood, but it appears to involve both genetic susceptibility and environmental factors. Treatment for PD that prevents neuronal death progression in the dopaminergic system and abnormal protein deposition in the brain is not yet available. Recently, mutations in the leucine-rich repeat kinase 2 (LRRK2) gene have been identified to cause autosomal-dominant late-onset PD and contribute to sporadic PD. Here, we review the recent models for LRRK2-linked Parkinsonism and their utility in studying LRRK2 neurobiology, pathogenesis, and potential therapeutics.

scholarly journals Calcineurin Controls Growth, Morphology, and Pathogenicity in Aspergillus fumigatus

2006 ◽  
Vol 5 (7) ◽  
pp. 1091-1103 ◽  
Author(s):  
William J. Steinbach ◽  
Robert A. Cramer ◽  
B. Zachary Perfect ◽  
Yohannes G. Asfaw ◽  
Theodor C. Sauer ◽  
...  
Keyword(s):  
Aspergillus Fumigatus ◽  
Clinical Observation ◽  
Immunocompromised Patient ◽  
Fungal Growth ◽  
Pathogenic Fungi ◽  
Wild Type ◽  
Therapeutic Approaches ◽  
Growth Morphology ◽  
Different Types ◽  
Hyphal Morphology

ABSTRACT Calcineurin is implicated in a myriad of human diseases as well as homeostasis and virulence in several major human pathogenic microorganisms. The fungus Aspergillus fumigatus is a leading cause of infectious death in the rapidly expanding immunocompromised patient population. Current antifungal treatments for invasive aspergillosis are often ineffective, and novel therapeutic approaches are urgently needed. We demonstrate that a mutant of A. fumigatus lacking the calcineurin A (cnaA) catalytic subunit exhibited defective hyphal morphology related to apical extension and polarized growth, which resulted in drastically decreased filamentation. The ΔcnaA mutant lacked the extensive lattice of invading hyphae seen with the wild-type and complemented strains. Sporulation was also affected in the ΔcnaA mutant, including morphological conidial defects with the absence of surface rodlets and the added presence of disjunctors creating long conidial chains. Infection with the ΔcnaA mutant in several distinct animal models with different types of immunosuppression and inoculum delivery led to a profound attenuation of pathogenicity compared to infection with the wild-type and complemented strains. Lung tissue from animals infected with the ΔcnaA mutant showed a complete absence of hyphae, in contrast to tissue from animals infected with the wild-type and complemented strains. Quantitative fungal burden and pulmonary infarct scoring confirmed these findings. Our results support the clinical observation that substantially decreasing fungal growth can prevent disease establishment and decrease mortality. Our findings reveal that calcineurin appears to play a globally conserved role in the virulence of several pathogenic fungi and yet plays specialized roles in each and can be an excellent target for therapeutic intervention.

scholarly journals A Novel LRRK2 Variant p.G2294R in the WD40 Domain Identified in Familial Parkinson’s Disease Affects LRRK2 Protein Levels

2021 ◽  
Vol 22 (7) ◽  
pp. 3708
Author(s):  
Jun Ogata ◽  
Kentaro Hirao ◽  
Kenya Nishioka ◽  
Arisa Hayashida ◽  
Yuanzhe Li ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Peripheral Blood ◽  
Kinase Activity ◽  
Late Onset ◽  
Causative Gene ◽  
Protein Levels ◽  
Wd40 Domain ◽  
Lrrk2 Protein ◽  
Familial Parkinson’S Disease

Leucine-rich repeat kinase 2 (LRRK2) is a major causative gene of late-onset familial Parkinson’s disease (PD). The suppression of kinase activity is believed to confer neuroprotection, as most pathogenic variants of LRRK2 associated with PD exhibit increased kinase activity. We herein report a novel LRRK2 variant—p.G2294R—located in the WD40 domain, detected through targeted gene-panel screening in a patient with familial PD. The proband showed late-onset Parkinsonism with dysautonomia and a good response to levodopa, without cognitive decline or psychosis. Cultured cell experiments revealed that p.G2294R is highly destabilized at the protein level. The LRRK2 p.G2294R protein expression was upregulated in the patient’s peripheral blood lymphocytes. However, macrophages differentiated from the same peripheral blood showed decreased LRRK2 protein levels. Moreover, our experiment indicated reduced phagocytic activity in the pathogenic yeasts and α-synuclein fibrils. This PD case presents an example wherein the decrease in LRRK2 activity did not act in a neuroprotective manner. Further investigations are needed in order to elucidate the relationship between LRRK2 expression in the central nervous system and the pathogenesis caused by altered LRRK2 activity.

scholarly journals Nucleus, Mitochondrion, or Reticulum? STAT3 à La Carte

2018 ◽  
Vol 19 (9) ◽  
pp. 2820 ◽  
Author(s):  
Lidia Avalle ◽  
Valeria Poli
Keyword(s):  
Energy Production ◽  
Energy Homeostasis ◽  
Multiple Roles ◽  
Pharmaceutical Companies ◽  
Signal Transducer ◽  
Post Translational Modifications ◽  
Pathological Conditions ◽  
Different Types ◽  
Tumor Transformation ◽  
Context Specific

The transcription factor signal transducer and activator of transcription (STAT)3 mediates the functions of cytokines, growth factors, and oncogenes under both physiological and pathological conditions. Uncontrolled/constitutive STAT3 activity is often detected in tumors of different types, where its role is mostly that of an oncogene, contributing in multiple ways to tumor transformation, growth, and progression. For this reason, many laboratories and pharmaceutical companies are making efforts to develop specific inhibitors. However, STAT3 has also been shown to act as a tumor suppressor in a number of cases, suggesting that its activity is strongly context-specific. Here, we discuss the bases that can explain the multiple roles of this factor in both physiological and pathological contexts. In particular, we focus on the following four features: (i) the distinct properties of the STAT3α and β isoforms; (ii) the multiple post-translational modifications (phosphorylation on tyrosine or serine, acetylation and methylation on different residues, and oxidation and glutathionylation) that can affect its activities downstream of multiple different signals; (iii) the non-canonical functions in the mitochondria, contributing to the maintenance of energy homeostasis under stress conditions; and (iv) the recently discovered functions in the endoplasmic reticulum, where STAT3 contributes to the regulation of calcium homeostasis, energy production, and apoptosis.

scholarly journals Analysis of the LRRK2 p.G2019S mutation in Colombian Parkinson’s Disease Patients

2015 ◽  
pp. 117-121 ◽  
Author(s):  
Andres Felipe Duque ◽  
Juan Carlos Lopez ◽  
Helena Hernandez ◽  
Bruno Benitez ◽  
Juan Jose Yunis ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson Disease ◽  
Latin American ◽  
Autosomal Dominant ◽  
Late Onset ◽  
Causal Factor ◽  
Leucine Rich Repeat ◽  
Common Cause ◽  
Asymptomatic Control ◽  
Normal Controls

Introduction: Mutations in the leucine-rich repeat kinase 2 gene (LRRK2 or Dardarin) are considered to be a common cause of autosomal dominant and sporadic Parkinson´s disease, but the prevalence of these mutations varies among populations. Objective: to analysed the frequency of the LRRK2 p.G2019S mutation (c.6055G>A transition) in a sample of Colombian patients. Materials and Methods: In the present study we have analysed the frequency of the LRRK2 p.G2019S mutation in 154 patients with familial or sporadic Parkinson Disease, including early and late onset patients, and 162 normal controls. Results: Our results show occurrence of this mutation in two cases (2/154, 1.3%) with classical Parkinson´s signs, and one completely asymptomatic control (1/162, 0.6%). Conclusion: The p.G2019S mutation is not an important causal factor of Parkinson Disease in Colombia having similar frequencies to those reported in other Latin American populations.

scholarly journals Arming the troops: Post-translational modification of extracellular bacterial proteins

2020 ◽  
Vol 103 (4) ◽  
pp. 003685042096431
Author(s):  
Suzanne Forrest ◽  
Martin Welch
Keyword(s):  
Cell Surface ◽  
Protein Secretion ◽  
Potential Functions ◽  
Post Translational Modification ◽  
Post Translational Modifications ◽  
Extracellular Milieu ◽  
Bacterial Proteins

Protein secretion is almost universally employed by bacteria. Some proteins are retained on the cell surface, whereas others are released into the extracellular milieu, often playing a key role in virulence. In this review, we discuss the diverse types and potential functions of post-translational modifications (PTMs) occurring to extracellular bacterial proteins.

scholarly journals Post-Translational Modifications of Extracellular Proteasome

Molecules ◽  
2020 ◽  
Vol 25 (15) ◽  
pp. 3504 ◽  
Author(s):  
Anna S. Tsimokha ◽  
Tatiana O. Artamonova ◽  
Egor E. Diakonov ◽  
Mikhail A. Khodorkovskii ◽  
Alexey N. Tomilin
Keyword(s):  
Extracellular Vesicles ◽  
Extracellular Space ◽  
Neurological Diseases ◽  
Prognostic Significance ◽  
Ubiquitin Proteasome System ◽  
Major Protein ◽  
Ion Cyclotron Resonance ◽  
Post Translational Modifications ◽  
Essential Components ◽  
Proteasome Subunits

The ubiquitin-proteasome system (UPS) is one of the major protein degradation pathways in eukaryotic cells. Abnormal functioning of this system has been observed in cancer and neurological diseases. The 20S proteasomes, essential components of the UPS, are present not only within the cells but also in the extracellular space, and their concentration in blood plasma has been found to be elevated and dependent upon the disease state, being of prognostic significance in patients suffering from cancer, liver diseases, and autoimmune diseases. However, functions of extracellular proteasomes and mechanisms of their release by cells remain largely unknown. The main mechanism of proteasome activity regulation is provided by modulation of their composition and post-translational modifications (PTMs). Moreover, diverse PTMs of proteins are known to participate in the loading of specific elements into extracellular vesicles. Since previous studies have revealed that the transport of extracellular proteasomes may occur via extracellular vesicles, we have set out to explore the PTMs of extracellular proteasomes in comparison to cellular counterparts. In this work, cellular and extracellular proteasomes were affinity purified and separated by SDS-PAGE for subsequent trypsinization and matrix-assisted laser desorption/ionization (MALDI) Fourier transform ion cyclotron resonance (FT-ICR) mass spectrometry (MS) analysis. In total, we could identify 64 and 55 PTM sites in extracellular and cellular proteasomes, respectively, including phosphorylation, ubiquitination, acetylation, and succinylation. We observed novel sites of acetylation at K238 and K192 of the proteasome subunits β2 and β3, respectively, that are specific for extracellular proteasomes. Moreover, cellular proteasomes show specific acetylation at K227 of α2 and ubiquitination at K201 of β3. Interestingly, succinylation of β6 at the residue K228 seems not to be present exclusively in extracellular proteasomes, whereas both extracellular and cellular proteasomes may also be acetylated at this site. The same situation takes place at K201 of the β3 subunit where ubiquitination is seemingly specific for cellular proteasomes. Moreover, crosstalk between acetylation, ubiquitination, and succinylation has been observed in the subunit α3 of both proteasome populations. These data will serve as a basis for further studies, aimed at dissection of the roles of extracellular proteasome-specific PTMs in terms of the function of these proteasomes and mechanism of their transport into extracellular space.

Problem behavior as a precursor of male criminality

1996 ◽  
Vol 8 (2) ◽  
pp. 443-455 ◽  
Author(s):  
Minna Hämäläinen ◽  
Lea Pulkkinen
Keyword(s):  
Early Adolescence ◽  
School Success ◽  
Late Onset ◽  
Teacher Rating ◽  
Criminal Records ◽  
Criminal Offenses ◽  
Peer Nomination ◽  
Different Types ◽  
Violent Offenses ◽  
Property Offenses

AbstractThe participants (originally 196 boys and 173 girls) in an ongoing longitudinal study were examined using peer nomination and teacher rating at ages 8 and 14 years. Criminal records were collected at age 27 years. The results showed that (a) criminal offenses were best predicted if the accumulation of behavior problems over the school years was considered; (b) the risk for different types of offenses was highest for boys who exhibited escalating conduct problems and school failure over the school years; (c) norm-breaking behavior in early adolescence was strongly related to a propensity to later criminal offenses; (d) childhood aggressiveness did not predict arrests without the presence of other problems. When followed by norm-breaking in early adolescence, it predicted violent offenses, and when followed by poor school success, it predicted property offenses; (e) interestingly, low prosociality turned out to have a significant independent relationship to arrests; and (f) the distinction between an early-onset path and a late-onset path proved to be valid.

scholarly journals Transcriptional responses to loss or gain of function of the leucine-rich repeat kinase 2 (LRRK2) gene uncover biological processes modulated by LRRK2 activity

2011 ◽  
Vol 21 (1) ◽  
pp. 163-174 ◽  
Author(s):  
Elena V. Nikonova ◽  
Yulan Xiong ◽  
Keith Q. Tanis ◽  
Valina L. Dawson ◽  
Robert L. Vogel ◽  
...  
Keyword(s):  
Biological Processes ◽  
Leucine Rich Repeat ◽  
Transcriptional Responses ◽  
Gain Of Function ◽  
Lrrk2 Gene

scholarly journals Comprehensive characterization and optimization of anti-LRRK2 (leucine-rich repeat kinase 2) monoclonal antibodies

2013 ◽  
Vol 453 (1) ◽  
pp. 101-113 ◽  
Author(s):  
Paul Davies ◽  
Kelly M. Hinkle ◽  
Nour N. Sukar ◽  
Bryan Sepulveda ◽  
Roxana Mesias ◽  
...  
Keyword(s):  
Monoclonal Antibodies ◽  
Human Brain ◽  
Brain Tissue ◽  
Kinase Activity ◽  
Expression Patterns ◽  
Significant Proportion ◽  
Leucine Rich Repeat ◽  
Human Brain Tissue ◽  
Robust Detection ◽  
Lrrk2 Protein

Missense mutations in LRRK2 (leucine-rich repeat kinase 2) are a major cause of PD (Parkinson's disease). Several antibodies against LRRK2 have been developed, but results using these polyclonal antibodies have varied widely leading to conflicting conclusions. To address this challenge, the Michael J. Fox Foundation for Parkinson's Research generated a number of monoclonal antibodies targeting epitopes across the LRRK2 protein. In the present paper, we report optimized protocols and results for ten monoclonal antibodies for immunoblotting, immunohistochemistry, immunoprecipitation and kinase activity assays, in rat, mouse and human brain tissue. Several efficacious antibodies were identified, but results demonstrate that the mouse monoclonal N241A/34 is suitable for most applications, with the best overall rabbit monoclonal antibody being c41-2. These antibodies produced a dominant band of the expected size via immunoblotting and a lack of labelling in tissue derived from LRRK2-knockout animals under optimized conditions. A significant proportion of LRRK2 protein localizes to insoluble fractions and no evidence of truncated LRRK2 protein was detected in any fraction from rodent or human tissues. An assay was developed for the robust detection of LRRK2 kinase activity directly from frozen mouse and human brain tissue, but precipitous declines in activity were observed that corresponded to increasing post-mortem intervals and processing times. Finally, we demonstrate the highest levels of brain-localized LRRK2 in the striatum, but note differential expression patterns between rat and mouse in both striatum and cortex. Anti-LRRK2 monoclonal antibodies that are unlimited in availability together with the proposed standardized protocols should aid in the definition of LRRK2 function in both health and disease.

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