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Adolfo M García, Lucas Sedeño, Natalia Trujillo, Yamile Bocanegra, Diana Gomez, David Pineda, Andrés Villegas, Edinson Muñoz, William Arias, Agustín Ibáñez
OBJECTIVES: The worldwide spread of Parkinson's disease (PD) calls for sensitive and specific measures enabling its early (or, ideally, preclinical) detection. Here, we use language measures revealing deficits in PD to explore whether similar disturbances are present in asymptomatic individuals at risk for the disease. METHODS: We administered executive, semantic, verb-production, and syntactic tasks to sporadic PD patients, genetic PD patients with PARK2 (parkin) or LRRK2 (dardarin) mutation, asymptomatic first-degree relatives of the latter with similar mutations, and socio-demographically matched controls...
February 2017: Journal of the International Neuropsychological Society: JINS
Andrés Felipe Duque, Juan Carlos Lopez, Bruno Benitez, Helena Hernandez, Juan José Yunis, William Fernandez, Humberto Arboleda, Gonzalo Arboleda
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 analyzed the frequency of the LRRK2 p.G2019S mutation (c.6055 G>A transition) in a sample of Colombian patients. METHODS: In the present study we have analyzed the frequency of the LRRK2 p...
September 30, 2015: Colombia Médica: CM
Manish Verma, Erin K Steer, Charleen T Chu
The leucine rich repeat kinase 2 (LRRK2/dardarin) is implicated in autosomal dominant familial and sporadic Parkinson's disease (PD); mutations in LRRK2 account for up to 40% of PD cases in some populations. LRRK2 is a large protein with a kinase domain, a GTPase domain, and multiple potential protein interaction domains. As such, delineating the functional pathways for LRRK2 and mechanisms by which PD-linked variants contribute to age-related neurodegeneration could result in pharmaceutically tractable therapies...
August 2014: Biochimica et Biophysica Acta
Giovanna Sanna, Maria Grazia Del Giudice, Claudia Crosio, Ciro Iaccarino
Mutations in LRRK2 (leucine-rich repeat kinase 2) (also known as PARK8 or dardarin) are responsible for the autosomal-dominant form of PD (Parkinson's disease). LRRK2 mutations were found in approximately 3-5% of familial and 1-3% of sporadic PD cases with the highest prevalence (up to 40%) in North Africans and Ashkenazi Jews. To date, mutations in LRRK2 are a major genetic risk factor for familial and sporadic PD. Despite the fact that 8 years have passed from the establishment of the first link between PD and dardarin in 2004, the pathophysiological role of LRRK2 in PD onset and progression is far from clearly defined...
October 2012: Biochemical Society Transactions
Jaya Sanyal, Biswanath Sarkar, Sabyasachi Ojha, Tapas Kumar Banerjee, Bidhan Chandra Ray, Vadlam Raghavendra Rao
BACKGROUND: Pathogenic mutations in leucine-rich repeat kinase 2 (LRRK2; PARK8) encoding dardarin, implicated in patients with autosomal dominant and sporadic Parkinson's disease (PD) among different ethnic groups (Ashkenazi Jews, North African Arabs, Basques) might be of some help in diagnostic screening and genetic counseling. AIM OF THE STUDY: We investigated the seven common mutations spanning exons 31, 35, and 41 reported in the LRRK2 gene among Eastern Indian patients with PD...
October 2010: Genetic Testing and Molecular Biomarkers
Tomoko Kanao, Katerina Venderova, David S Park, Terry Unterman, Bingwei Lu, Yuzuru Imai
Missense mutations in leucine-rich repeat kinase 2 (LRRK2)/Dardarin gene, the product of which encodes a kinase with multiple domains, are known to cause autosomal dominant late onset Parkinson's disease (PD). In the current study, we report that the gene product LRRK2 directly phosphorylates the forkhead box transcription factor FoxO1 and enhances its transcriptional activity. This pathway was found to be conserved in Drosophila, as the Drosophila LRRK2 homolog (dLRRK) enhanced the neuronal toxicity of FoxO...
October 1, 2010: Human Molecular Genetics
José-Félix Martí-Massó, Javier Ruiz-Martínez, Maria J Bolaño, Irune Ruiz, Ana Gorostidi, Fermin Moreno, Isidre Ferrer, Adolfo López de Munain
We report the neuropathological findings in a patient with Parkinson's disease (PD) associated with Basque R1441G-LRRK2/dardarin mutation. The patient was a man with disease onset at 68 years of age, with unilateral rest tremor; the Parkinsonism was well controlled with medication for 15 years. He died at the age of 86, after 18 years of evolution. The neuropathological examination disclosed mild neuronal loss in the substantia nigra pars compacta without alpha-synuclein, tau, LRRK2, or ubiquitin cytoplasmic inclusions...
October 15, 2009: Movement Disorders: Official Journal of the Movement Disorder Society
M A Mena, J A Rodriguez-Navarro, R Ros, J G de Yebenes
Parkinson's disease (PD) is a neurodegenerative disorder affecting nearly 3 million patients in Europe and North America, characterized by a core phenotype of motor deficits, akinesia, rigidity, postural disturbance and tremor, which is complicated by other neurological deficits during its long progression. Our knowledge about the pathophisiology of PD was limited, up to 25 years ago, to the observation of the lesion of the nigro-striatal dopamine neurons in these patients. The subjects who developed PD as a consequence of exposure to neurotoxic compounds, increased our knowledge about the pathogenesis of this disease...
2008: Current Medicinal Chemistry
Juan C Gómez-Esteban, Elena Lezcano, Juan J Zarranz, Carmen González, Gaizka Bilbao, Imanol Lambarri, Olivia Rodríguez, Jesús Garibi
OBJECTIVE: Deep brain subthalamic stimulation provides symptomatic relief to patients with Parkinson's disease. The present study analyzes the postoperative outcome of deep brain subthalamic stimulation in patients carrying the R1441G mutation in the leucine-rich repeat kinase-2 (LRRK2) (dardarin) gene. METHODS: Five of the 48 patients treated in our unit carried a mutation in the LRRK2 (dardarin) gene. All five met the Core Assessment Program for Surgical Interventional Therapies criteria for inclusion in the surgical program...
April 2008: Neurosurgery
S N Pchelina, A F Yakimovskii, A K Emelyanov, O N Ivanova, A L Schwarzman, A B Singleton
BACKGROUND AND PURPOSE: Mutations in LRRK2, encoding leucine-rich repeat kinase 2 (or Dardarin), cause autosomal dominant Parkinson's disease (AdPD) and are also found in sporadic PD (sPD). To investigate the frequency of LRRK2 mutations in a sample of Russian PD patients. METHODS: We sequenced the complete coding region of LRRK2 in 65 patients with AdPD and in 30 patients with sPD. Furthermore, in 20 patients with AdPD and in 159 patients with sPD we screened several common LRRK2 mutations (G2019S, R1441C/G/H, I2012T and I2020T)...
July 2008: European Journal of Neurology: the Official Journal of the European Federation of Neurological Societies
Coro Paisán-Ruíz, Priti Nath, Nicole Washecka, J Raphael Gibbs, Andrew B Singleton
Mutation of LRRK2, encoding dardarin, is the most common known genetic cause of Parkinson's disease (PD). The large size of this gene and the relative ease with which the most common mutations can be screened means that although more than 50 LRRK2 screening papers have been published, few have analyzed the entire coding sequence. Furthermore, no comprehensive sequence-based analysis has been performed on control samples. Here, we present sequencing of all coding exons in a series of 275 PD cases and 275 neurologically normal controls and analysis of the LRRK2 locus for whole gene multiplications or deletions...
April 2008: Human Mutation
Cristine Alves da Costa
Parkinson's disease (PD) is a movement disorder of high prevalence in the elderly. It is characterized by a loss of dopaminergic neurons and the presence of intracytoplasmic inclusions named Lewy bodies. To date six familial PD-associated proteins have been identified so far. Some of them are implicated in the development of either autosomal dominant (alpha-synuclein and LRRK2 (leucine-rich repeat kinase 2/dardarin) or early-onset recessive (parkin, DJ-1, PINK1 (PTEN-induced kinase-1) and ATP13A2) PD forms...
November 2007: Current Molecular Medicine
Janel Johnson, Coro Paisán-Ruíz, Grisel Lopez, Cynthia Crews, Angela Britton, Roniel Malkani, E Whitney Evans, Aideen McInerney-Leo, Shushant Jain, Robert L Nussbaum, Kelly D Foote, Ronald J Mandel, Anthony Crawley, Sharon Reimsnider, Hubert H Fernandez, Michael S Okun, Katrina Gwinn-Hardy, Andrew B Singleton
BACKGROUND: Recently, mutations in LRRK2 encoding the protein dardarin have been linked to an autosomal dominant form of parkinsonism. OBJECTIVE: To identify mutations causing Parkinson's disease (PD) in a cohort of North Americans with familial PD. METHODS: We sequenced exons 1-51 of LRRK2 in 79 unrelated North American PD patients reporting a family history of the disease. RESULTS: One patient had a missense mutation (Thr2356Ile) while two others had the common Gly2019Ser mutation...
2007: Neuro-degenerative Diseases
Elisa Greggio, Patrick A Lewis, Marcel P van der Brug, Rili Ahmad, Alice Kaganovich, Jinhui Ding, Alexandra Beilina, Acacia K Baker, Mark R Cookson
Several mutations have been found in the leucine-rich repeat kinase 2 gene (LRRK2), encoding the protein dardarin, which are associated with autosomal dominant Parkinson disease. We have previously shown that mutant LRRK2/dardarin is toxic to neurons and neuron-like cell lines in culture and that some mutations are also associated with an inclusion-body phenotype. There is a homologous kinase, LRRK1, which has a similar domain structure but is not known to carry mutations causing Parkinson disease. In the current study, we introduced mutations at equivalent residues in both LRRK2 and LRRK1 to determine their effects in cells...
July 2007: Journal of Neurochemistry
S Scholz, R J Mandel, H H Fernandez, K D Foote, R L Rodriguez, E Barton, S Munson, A Singleton, M S Okun
In the last decade, major breakthroughs in the understanding of genetic contributions to Parkinson's disease (PD) have been achieved. Recently, mutations in LRRK2, encoding dardarin, have been found to be responsible for an autosomal dominant parkinsonism (OMIM 607060). We screened 311 subjects (cases: n = 202, controls: n = 109) for the three previously reported LRRK2 mutations. Our investigation revealed a sporadic case of PD with a heterozygous mutation G2019S (c.6055G>A). Here, we present the clinical phenotype of this patient and discuss the implications of genetic testing for the G2019S mutation in patients with sporadic PD...
December 2006: European Journal of Neurology: the Official Journal of the European Federation of Neurological Societies
Nirit Lev, Dusan Roncevic, Dusan Roncevich, Debby Ickowicz, Eldad Melamed, Daniel Offen
Parkinson's disease (PD), one of the most common neurodegenerative diseases, is a multifactorial disease caused by both genetic and environmental factors. Although most patients suffering from PD have a sporadic disease, several genetic causes have been identified in recent years, including alpha-synuclein, parkin, PINK1, dardarin (LRRK2), and DJ-1. DJ-1 deletions and point mutations have been found worldwide, and loss of functional protein was shown to cause autosomal recessive PD. Moreover, DJ-1 immunoreactive inclusions are found in other alpha-synucleopathies and tauopathies, indicating that different neurodegenerative diseases might share a common mechanism in which DJ-1 might play a key role...
2006: Journal of Molecular Neuroscience: MN
Javier Simón-Sánchez, José-Félix Martí-Massó, José Vicente Sánchez-Mut, Coro Paisán-Ruiz, Angel Martínez-Gil, Javier Ruiz-Martínez, Amets Sáenz, Andrew B Singleton, Adolfo López de Munain, Jordi Pérez-Tur
The recent discovery of mutations in Dardarin (LRRK2) have been related to the appearance of Parkinson's disease in several families. Notably, one single mutation in this gene (R1441G) not only appeared in familial, but also in apparently sporadic Parkinson disease (PD) patients of Basque descent. A clinical population was ascertained, and subjects were classified into Basque and non-Basque descent according to their known ancestry. The R1441G mutation was assayed using an allele-specific polymerase chain reaction, and several single nucleotide polymorphisms surrounding this mutation were analyzed by direct sequencing...
November 2006: Movement Disorders: Official Journal of the Movement Disorder Society
R J Dinis-Oliveira, F Remião, H Carmo, J A Duarte, A Sánchez Navarro, M L Bastos, F Carvalho
Parkinson's disease (PD) is a multifactorial chronic progressive neurodegenerative disease influenced by age, and by genetic and environmental factors. The role of genetic predisposition in PD has been increasingly acknowledged and a number of relevant genes have been identified (e.g., genes encoding alpha-synuclein, parkin, and dardarin), while the search for environmental factors that influence the pathogenesis of PD has only recently begun to escalate. In recent years, the investigation on paraquat (PQ) toxicity has suggested that this herbicide might be an environmental factor contributing to this neurodegenerative disorder...
December 2006: Neurotoxicology
Elisa Greggio, Shushant Jain, Ann Kingsbury, Rina Bandopadhyay, Patrick Lewis, Alice Kaganovich, Marcel P van der Brug, Alexandra Beilina, Jeff Blackinton, Kelly Jean Thomas, Rili Ahmad, David W Miller, Sashi Kesavapany, Andrew Singleton, Andrew Lees, Robert J Harvey, Kirsten Harvey, Mark R Cookson
Mutations in the LRRK2 gene, coding for dardarin, cause dominantly inherited Parkinson's disease (PD). Dardarin is a large protein, and mutations are found throughout the gene including the kinase domain. However, it is not clear if kinase activity is important for the damaging effects of pathogenic mutations. In this study, we noted two cellular phenotypes associated with mutant dardarin. First, pathogenic mutations increase the tendency of dardarin to form inclusion bodies. Secondly, neurons and neuronal cell lines undergo cell death after expression of mutant protein...
August 2006: Neurobiology of Disease
Mark R Cookson, Georgia Xiromerisiou, Andrew Singleton
PURPOSE OF REVIEW: Rapid progress in genetics has meant that there are now five genes identified for 'Parkinson's disease'. The detailed phenotypes vary, but generally the dominant genes cause a Lewy body disease spectrum whereas recessive genes cause a milder parkinsonism with variable inclusion body pathology. The subject of this review is to highlight these discoveries and to discuss their relationships to idiopathic Parkinson's disease. RECENT FINDINGS: In January 2004, mutations in PINK1, coding for a mitochondrial kinase, were found to be causal for recessive parkinsonism...
December 2005: Current Opinion in Neurology
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