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https://www.readbyqxmd.com/read/29054882/parkinson-s-disease-associated-lrrk2-hyperactive-kinase-mutant-disrupts-synaptic-vesicle-trafficking-in-ventral-midbrain-neurons
#1
Ping-Yue Pan, Xianting Li, Jing Wang, James Powell, Qian Wang, Yuanxi Zhang, Zhaoyu Chen, Bridget Wicinski, Patrick Hof, Timothy A Ryan, Zhenyu Yue
Parkinson's disease (PD) is characterized pathologically by the selective loss of substantia nigra (SN) dopaminergic (DAergic) neurons. Recent evidence has suggested a role of LRRK2, linked to the most frequent familial PD, in regulating synaptic vesicle (SV) trafficking. However, the mechanism whereby LRRK2 mutants contribute to nigral vulnerability remains unclear. Here we show that the most common PD mutation LRRK2 G2019S impairs SV endocytosis in ventral midbrain (MB) neurons including DA neurons, and the slowed endocytosis can be rescued by inhibition of LRRK2 kinase activity...
October 20, 2017: Journal of Neuroscience: the Official Journal of the Society for Neuroscience
https://www.readbyqxmd.com/read/29038245/mitochondrial-calcium-dysregulation-contributes-to-dendrite-degeneration-mediated-by-pd-lbd-associated-lrrk2-mutants
#2
Manish Verma, Jason Callio, P Anthony Otero, Israel Sekler, Zachary P Wills
Mutations in leucine-rich repeat kinase 2 (LRRK2) contribute to development of late-onset familial Parkinson's disease (PD), with clinical features of motor and cognitive dysfunction indistinguishable from sporadic PD. Calcium dysregulation plays an important role in PD pathogenesis, but the mechanisms of neurodegeneration remain unclear. Recent reports indicate enhanced excitatory neurotransmission in cortical neurons expressing mutant LRRK2, which occurs prior to the well-characterized phenotype of dendritic shortening...
October 16, 2017: Journal of Neuroscience: the Official Journal of the Society for Neuroscience
https://www.readbyqxmd.com/read/29029963/genetic-risk-factors-in-finnish-patients-with-parkinson-s-disease
#3
Susanna Ylönen, Ari Siitonen, Michael A Nalls, Pauli Ylikotila, Jaana Autere, Johanna Eerola-Rautio, Raphael Gibbs, Mikko Hiltunen, Pentti J Tienari, Hilkka Soininen, Andrew B Singleton, Kari Majamaa
INTRODUCTION: Variation contributing to the risk of Parkinson's disease (PD) has been identified in several genes and at several loci including GBA, SMPD1, LRRK2, POLG1, CHCHD10 and MAPT, but the frequencies of risk variants seem to vary according to ethnic background. Our aim was to analyze how variation in these genes contributes to PD in the Finnish population. METHODS: The subjects consisted of 527 Finnish patients with early-onset PD, 325 patients with late-onset PD and 403 population controls...
September 29, 2017: Parkinsonism & related Disorders
https://www.readbyqxmd.com/read/29023112/design-of-leucine-rich-repeat-kinase-2-lrrk2-inhibitors-using-a-crystallographic-surrogate-derived-from-checkpoint-kinase-1-chk1
#4
Douglas S Williamson, Garrick P Smith, Pamela Acheson-Dossang, Simon T Bedford, Victoria Chell, I-Jen Chen, Justus C A Daechsel, Zoe Daniels, Laurent David, Pawel Dokurno, Morten Hentzer, Martin C Herzig, Roderick E Hubbard, Jonathan D Moore, James B Murray, Samantha Newland, Stuart C Ray, Terry Shaw, Allan E Surgenor, Lindsey Terry, Kenneth Thirstrup, Yikang Wang, Kenneth V Christensen
Mutations in leucine-rich repeat kinase 2 (LRRK2), such as G2019S, are associated with an increased risk of developing Parkinson's disease. Surrogates for the LRRK2 kinase domain based on checkpoint kinase 1 (CHK1) mutants were designed, expressed in insect cells infected with baculovirus, purified and crystallized. X-ray structures of the surrogates complexed with known LRRK2 inhibitors rationalized compound potency and selectivity. The CHK1 10-point mutant was preferred, following assessment of surrogate binding affinity with LRRK2 inhibitors...
October 12, 2017: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28973664/lrrk2-g2019s-induced-mitochondrial-dna-damage-is-lrrk2-kinase-dependent-and-inhibition-restores-mtdna-integrity-in-parkinson-s-disease
#5
Evan H Howlett, Nicholas Jensen, Frances Belmonte, Faria Zafar, Xiaoping Hu, Jillian Kluss, Birgitt Schüle, Brett A Kaufman, J Timothy Greenamyre, Laurie H Sanders
Mutations in leucine-rich repeat kinase 2 (LRRK2) are associated with increased risk for developing Parkinson's disease (PD). Previously we found that LRRK2 G2019S mutation carriers have increased mitochondrial DNA (mtDNA) damage and after zinc finger nuclease-mediated gene mutation correction, mtDNA damage was no longer detectable. While the mtDNA damage phenotype can be unambiguously attributed to the LRRK2 G2019S mutation, the underlying mechanism(s) is unknown. Here, we examine the role of LRRK2 kinase function in LRRK2 G2019S-mediated mtDNA damage, using both genetic and pharmacological approaches in cultured neurons and PD patient-derived cells...
August 14, 2017: Human Molecular Genetics
https://www.readbyqxmd.com/read/28958936/suppression-of-neuroinflammation-by-matrix-metalloproteinase-8-inhibitor-in-aged-normal-and-lrrk2-g2019s-parkinson-s-disease-model-mice-challenged-with-lipopolysaccharide
#6
Jisun Kim, Yeon-Hui Jeong, Eun-Jung Lee, Jin-Sun Park, Hyemyung Seo, Hee-Sun Kim
Microglial priming is caused by aging and neurodegenerative diseases, and is characterized by an exaggerated microglial inflammatory response to secondary and sub-threshold challenges. In the present study, we examined the effects of the matrix metalloproteinase-8 (MMP-8) inhibitor (M8I) on the brain of aged normal and leucine-rich repeat kinase 2 (LRRK2) G2019S Parkinson's disease (PD) model mice systemically stimulated with lipopolysaccharide (LPS). The results indicated that Iba-1 positive microglia and GFAP-positive astrocytes, which were increased by LPS, significantly decreased by M8I in aged normal and PD model mice...
November 18, 2017: Biochemical and Biophysical Research Communications
https://www.readbyqxmd.com/read/28930069/initial-elevations-in-glutamate-and-dopamine-neurotransmission-decline-with-age-as-does-exploratory-behavior-in-lrrk2-g2019s-knock-in-mice
#7
Mattia Volta, Dayne A Beccano-Kelly, Sarah A Paschall, Stefano Cataldi, Sarah E MacIsaac, Naila Kuhlmann, Chelsie A Kadgien, Igor Tatarnikov, Jesse Fox, Jaskaran Khinda, Emma Mitchell, Sabrina Bergeron, Heather Melrose, Matthew J Farrer, Austen J Milnerwood
LRRK2 mutations produce end-stage Parkinson's disease (PD) with reduced nigrostriatal dopamine, whereas, asymptomatic carriers have increased dopamine turnover and altered brain connectivity. LRRK2 pathophysiology remains unclear, but reduced dopamine and mitochondrial abnormalities occur in aged G2019S mutant knock-in (GKI) mice. Conversely, cultured GKI neurons exhibit increased synaptic transmission. We assessed behavior and synaptic glutamate and dopamine function across a range of ages. Young GKI mice exhibit more vertical exploration, elevated glutamate and dopamine transmission, and aberrant D2-receptor responses...
September 20, 2017: ELife
https://www.readbyqxmd.com/read/28893563/the-impact-of-murine-lrrk2-g2019s-transgene-overexpression-on-acute-responses-to-inflammatory-challenge
#8
Darcy Litteljohn, Chris Rudyk, Zach Dwyer, Kyle Farmer, Teresa Fortin, Shawn Hayley
The most common Parkinson's disease (PD) mutation is the gain-of-function LRRK2 G2019S variant, which has also been linked to inflammatory disease states. Yet, little is known of the role of G2019S in PD related complex behavioral or immune/hormonal processes in response to inflammatory/toxicant challenges. Hence, we characterized the behavioural, neuroendocrine-immune and central monoaminergic responses in G2019S overexpressing mutants following systemic interferon-gamma (IFN-γ) or lipopolysaccharide (LPS) administration...
September 8, 2017: Brain, Behavior, and Immunity
https://www.readbyqxmd.com/read/28864907/alterations-in-the-reduced-pteridine-contents-in-the-cerebrospinal-fluids-of-lrrk2-mutation-carriers-and-patients-with-parkinson-s-disease
#9
Hiroshi Ichinose, Ken-Ichi Inoue, Shinobu Arakawa, Yuki Watanabe, Hiroki Kurosaki, Shoko Koshiba, Eldbjorg Hustad, Masahiko Takada, Jan O Aasly
Tetrahydrobiopterin (BH4) is a cofactor for tyrosine hydroxylase that is essential for the biosynthesis of dopamine. Parkinson's disease (PD) is characterized by a progressive degeneration of nigrostriatal dopaminergic neurons, and biomarkers reflecting the degree of neurodegeneration are important not only for basic research but also for clinical diagnosis and the treatment of the disease. Although the total neopterin and biopterin levels in the cerebrospinal fluids (CSF) of the patients with PD were reported, alterations in the composition of reduced and oxidized forms of pteridine compounds have not been examined...
September 1, 2017: Journal of Neural Transmission
https://www.readbyqxmd.com/read/28751472/parkinson-disease-associated-lrrk2-g2019s-transgene-disrupts-marrow-myelopoiesis-and-peripheral-th17-response
#10
Jeongho Park, Jang-Won Lee, Scott C Cooper, Hal E Broxmeyer, Jason R Cannon, Chang H Kim
Parkinson's disease (PD) is a neurodegenerative disease, whereas Crohn's disease is an inflammatory bowel disease. Interestingly, polymorphisms in the LRRK2 gene have been identified as risk factors for both diseases. LRRK2 G2019S is the most prevalent mutation found in PD. To gain insights into the role of the LRRK2 G2019S gene on the development and activation of the immune system in the brain-gut axis, we investigated the effect of LRRK2 G2019S on bone marrow myeloid progenitors and myeloid cell function in the periphery...
October 2017: Journal of Leukocyte Biology
https://www.readbyqxmd.com/read/28723952/evidence-for-prehistoric-origins-of-the-g2019s-mutation-in-the-north-african-berber-population
#11
Rafiqua Ben El Haj, Ayyoub Salmi, Wafa Regragui, Ahmed Moussa, Naima Bouslam, Houyam Tibar, Ali Benomar, Mohamed Yahyaoui, Ahmed Bouhouche
The most common cause of the monogenic form of Parkinson's disease known so far is the G2019S mutation of the leucine-rich repeat kinase 2 (LRRK2) gene. Its frequency varies greatly among ethnic groups and geographic regions ranging from less than 0.1% in Asia to 40% in North Africa. This mutation has three distinct haplotypes; haplotype 1 being the oldest and most common. Recent studies have dated haplotype 1 of the G2019S mutation to about 4000 years ago, but it remains controversial whether the mutation has a Near-Eastern or Moroccan-Berber ancestral origin...
2017: PloS One
https://www.readbyqxmd.com/read/28720718/phosphorylation-of-amyloid-precursor-protein-by-mutant-lrrk2-promotes-aicd-activity-and-neurotoxicity-in-parkinson-s-disease
#12
Zhong-Can Chen, Wei Zhang, Ling-Ling Chua, Chou Chai, Rong Li, Lin Lin, Zhen Cao, Dario C Angeles, Lawrence W Stanton, Jian-He Peng, Zhi-Dong Zhou, Kah-Leong Lim, Li Zeng, Eng-King Tan
Mutations in LRRK2, which encodes leucine-rich repeat kinase 2, are the most common genetic cause of familial and sporadic Parkinson's disease (PD), a degenerative disease of the central nervous system that causes impaired motor function and, in advanced stages, dementia. Dementia is a common symptom of another neurodegenerative disease, Alzheimer's disease, and research suggests that there may be pathophysiological and genetic links between the two diseases. Aggregates of β amyloid [a protein produced through cleavage of amyloid precursor protein (APP)] are seen in both diseases and in PD patients carrying G2019S-mutant LRRK2...
July 18, 2017: Science Signaling
https://www.readbyqxmd.com/read/28683740/using-kasp-technique-to-screen-lrrk2-g2019s-mutation-in-a-large-tunisian-cohort
#13
Zied Landoulsi, Sawssan Benromdhan, Mouna Ben Djebara, Mariem Damak, Hamza Dallali, Rym Kefi, Sonia Abdelhak, Amina Gargouri-Berrechid, Chokri Mhiri, Riadh Gouider
BACKGROUND: In North African populations, G2019S mutation in LRRK2 gene, encoding for the leucine-rich repeat kinase 2, is the most prevalent mutation linked to familial and sporadic Parkinson's disease (PD). Early detection of G2019S by fast genetic testing is very important to guide PD's diagnosis and support patients and their family caregivers for better management of their life according to disease's evolution. METHODS: In our study, a genetic PD's diagnosis tool was developed for large scale genotyping using Kompetitive Allele Specific PCR (KASP) technology...
July 6, 2017: BMC Medical Genetics
https://www.readbyqxmd.com/read/28679601/prospective-clinical-and-dat-spect-imaging-in-premotor-lrrk2-g2019s-associated-parkinson-disease
#14
María Sierra, Isabel Martínez-Rodríguez, Pascual Sánchez-Juan, Isabel González-Aramburu, Mikel Jiménez-Alonso, Antonio Sánchez-Rodríguez, José Berciano, Ignacio Banzo, Jon Infante
OBJECTIVE: To assess the value of baseline clinical and imaging biomarkers in a cohort of asymptomatic LRRK2 G2019S carriers for predicting conversion to Parkinson disease (PD) at 4 years. METHODS: Thirty-two asymptomatic carriers of LRRK2 G2019S mutation underwent baseline and 4-year evaluation including clinical examination (Unified Parkinson's Disease Rating Scale, part III, olfaction University of Pennsylvania Smell Identification Test [UPSIT]) and dopamine transporter (DaT) SPECT ((123)I-ioflupane)...
August 1, 2017: Neurology
https://www.readbyqxmd.com/read/28656686/estimation-of-genetic-risk-function-with-covariates-in-the-presence-of-missing-genotypes
#15
Annie J Lee, Karen Marder, Roy N Alcalay, Helen Mejia-Santana, Avi Orr-Urtreger, Nir Giladi, Susan Bressman, Yuanjia Wang
In genetic epidemiological studies, family history data are collected on relatives of study participants and used to estimate the age-specific risk of disease for individuals who carry a causal mutation. However, a family member's genotype data may not be collected because of the high cost of in-person interview to obtain blood sample or death of a relative. Previously, efficient nonparametric genotype-specific risk estimation in censored mixture data has been proposed without considering covariates. With multiple predictive risk factors available, risk estimation requires a multivariate model to account for additional covariates that may affect disease risk simultaneously...
September 30, 2017: Statistics in Medicine
https://www.readbyqxmd.com/read/28649619/variable-frequency-of-lrrk2-variants-in-the-latin-american-research-consortium-on-the-genetics-of-parkinson-s-disease-large-pd-a-case-of-ancestry
#16
Mario Cornejo-Olivas, Luis Torres, Mario R Velit-Salazar, Miguel Inca-Martinez, Pilar Mazzetti, Carlos Cosentino, Federico Micheli, Claudia Perandones, Elena Dieguez, Victor Raggio, Vitor Tumas, Vanderci Borges, Henrique B Ferraz, Carlos R M Rieder, Artur Shumacher-Schuh, Carlos Velez-Pardo, Marlene Jimenez-Del-Rio, Francisco Lopera, Jorge Chang-Castello, Brennie Andreé-Munoz, Sarah Waldherr, Dora Yearout, Cyrus P Zabetian, Ignacio F Mata
Mutations in Leucine-Rich Repeat Kinase 2 (LRRK2), primarily located in codons G2019 and R1441, represent the most common genetic cause of Parkinson's disease in European-derived populations. However, little is known about the frequency of these mutations in Latin American populations. In addition, a prior study suggested that a LRRK2 polymorphism (p.Q1111H) specific to Latino and Amerindian populations might be a risk factor for Parkinson's disease, but this finding requires replication. We screened 1734 Parkinson's disease patients and 1097 controls enrolled in the Latin American Research Consortium on the Genetics of Parkinson's disease (LARGE-PD), which includes sites in Argentina, Brazil, Colombia, Ecuador, Peru, and Uruguay...
2017: NPJ Parkinson's Disease
https://www.readbyqxmd.com/read/28639421/penetrance-estimate-of-lrrk2-p-g2019s-mutation-in-individuals-of-non-ashkenazi-jewish-ancestry
#17
Annie J Lee, Yuanjia Wang, Roy N Alcalay, Helen Mejia-Santana, Rachel Saunders-Pullman, Susan Bressman, Jean-Christophe Corvol, Alexis Brice, Suzanne Lesage, Graziella Mangone, Eduardo Tolosa, Claustre Pont-Sunyer, Dolores Vilas, Birgitt Schüle, Farah Kausar, Tatiana Foroud, Daniela Berg, Kathrin Brockmann, Stefano Goldwurm, Chiara Siri, Rosanna Asselta, Javier Ruiz-Martinez, Elisabet Mondragón, Connie Marras, Taneera Ghate, Nir Giladi, Anat Mirelman, Karen Marder
BACKGROUND: Penetrance estimates of the leucine-rich repeat kinase 2 (LRRK2) p.G2019S mutation for PD vary widely (24%-100%). The p.G2019S penetrance in individuals of Ashkenazi Jewish ancestry has been estimated as 25%, adjusted for multiple covariates. It is unknown whether penetrance varies among different ethnic groups. The objective of this study was to estimate the penetrance of p.G2019S in individuals of non-Ashkenazi Jewish ancestry and compare penetrance between Ashkenazi Jews and non-Ashkenazi Jews to age 80...
June 22, 2017: Movement Disorders: Official Journal of the Movement Disorder Society
https://www.readbyqxmd.com/read/28588547/improving-dual-task-walking-paradigms-to-detect-prodromal-parkinson-s-and-alzheimer-s-diseases
#18
Maroua Belghali, Nathalie Chastan, Damien Davenne, Leslie M Decker
Gait control is a complex movement, relying on spinal, subcortical, and cortical structures. The presence of deficits in one or more of these structures will result in changes in gait automaticity and control, as is the case in several neurodegenerative diseases, such as Alzheimer's disease (AD) and Parkinson's disease (PD). By reviewing recent findings in this field of research, current studies have shown that gait performance assessment under dual-task conditions could contribute to predict both of these diseases...
2017: Frontiers in Neurology
https://www.readbyqxmd.com/read/28582422/role-of-lrrk2-in-the-regulation-of-dopamine-receptor-trafficking
#19
Mauro Rassu, Maria Grazia Del Giudice, Simona Sanna, Jean Marc Taymans, Michele Morari, Alberto Brugnoli, Martina Frassineti, Alessandra Masala, Sonia Esposito, Manuela Galioto, Cristiana Valle, Maria Teresa Carri, Alice Biosa, Elisa Greggio, Claudia Crosio, Ciro Iaccarino
Mutations in LRRK2 play a critical role in both familial and sporadic Parkinson's disease (PD). Up to date, the role of LRRK2 in PD onset and progression remains largely unknown. However, experimental evidence highlights a critical role of LRRK2 in the control of vesicle trafficking that in turn may regulate different aspects of neuronal physiology. We have analyzed the role of LRRK2 in regulating dopamine receptor D1 (DRD1) and D2 (DRD2) trafficking. DRD1 and DRD2 are the most abundant dopamine receptors in the brain...
2017: PloS One
https://www.readbyqxmd.com/read/28487191/human-lrrk2-g2019s-mutation-represses-post-synaptic-protein-psd95-and-causes-cognitive-impairment-in-transgenic-mice
#20
Samuel O Adeosun, Xu Hou, Baoying Zheng, Heather L Melrose, Thomas Mosley, Jun Ming Wang
BACKGROUND: LRRK2 G2019S mutation is associated with increased kinase activity and is the most common mutation associated with late-onset PD. However, the transgenic mouse model has not recapitulated cardinal PD-related motor phenotypes. Non-motor symptoms of PD including cognitive impairments are very common and may appear earlier than the motor symptoms. The objective of this study was to determine whether human LRRK2 with G2019S mutation causes hippocampus-dependent cognitive deficits in mice...
July 2017: Neurobiology of Learning and Memory
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