scholarly journals The function of orthologues of the human Parkinson's disease gene LRRK2 across species: implications for disease modelling in preclinical research

2016 ◽  
Vol 473 (3) ◽  
pp. 221-232 ◽  
Author(s):  
Rebekah G. Langston ◽  
Iakov N. Rudenko ◽  
Mark R. Cookson
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Animal Models ◽  
Autosomal Dominant ◽  
Disease Gene ◽  
Late Onset ◽  
Biochemical Properties ◽  
Leucine Rich Repeat ◽  
Causal Gene ◽  
Preclinical Research

In the period since LRRK2 (leucine-rich repeat kinase 2) was identified as a causal gene for late-onset autosomal dominant parkinsonism, a great deal of work has been aimed at understanding whether the LRRK2 protein might be a druggable target for Parkinson's disease (PD). As part of this effort, animal models have been developed to explore both the normal and the pathophysiological roles of LRRK2. However, LRRK2 is part of a wider family of proteins whose functions in different organisms remain poorly understood. In this review, we compare the information available on biochemical properties of LRRK2 homologues and orthologues from different species from invertebrates (e.g. Caenorhabditis elegans and Drosophila melanogaster) to mammals. We particularly discuss the mammalian LRRK2 homologue, LRRK1, and those species where there is only a single LRRK homologue, discussing examples where each of the LRRK family of proteins has distinct properties as well as those cases where there appear to be functional redundancy. We conclude that uncovering the function of LRRK2 orthologues will help to elucidate the key properties of human LRRK2 as well as to improve understanding of the suitability of different animal models for investigation of LRRK2-related PD.

scholarly journals Inflammatory bowel disease and Parkinson’s disease: common pathophysiological links

Gut ◽  
2020 ◽  
pp. gutjnl-2020-322429 ◽  
Author(s):  
Ho-Su Lee ◽  
Evy Lobbestael ◽  
Séverine Vermeire ◽  
João Sabino ◽  
Isabelle Cleynen
Keyword(s):  
Parkinson’S Disease ◽  
Inflammatory Bowel Disease ◽  
Parkinson's Disease ◽  
Bowel Disease ◽  
Population Based ◽  
Leucine Rich Repeat ◽  
Causal Gene ◽  
Genetic Studies ◽  
Inflammatory Bowel ◽  
Shared Genetic

Inflammatory bowel disease and Parkinson’s disease are chronic progressive disorders that mainly affect different organs: the gut and brain, respectively. Accumulating evidence has suggested a bidirectional link between gastrointestinal inflammation and neurodegeneration, in accordance with the concept of the ‘gut–brain axis’. Moreover, recent population-based studies have shown that inflammatory bowel disease might increase the risk of Parkinson's disease. Although the precise mechanisms underlying gut–brain interactions remain elusive, some of the latest findings have begun to explain the link. Several genetic loci are shared between both disorders with a similar direction of effect on the risk of both diseases. The most interesting example is LRRK2 (leucine-rich repeat kinase 2), initially identified as a causal gene in Parkinson's disease, and recently also implicated in Crohn’s disease. In this review, we highlight recent findings on the link between these seemingly unrelated diseases with shared genetic susceptibility. We discuss supporting and conflicting data obtained from epidemiological and genetic studies along with remaining questions and concerns. In addition, we discuss possible biological links including the gut–brain axis, microbiota, autoimmunity, mitochondrial function and autophagy.

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.

Genetic Insights into Early-onset Parkinson’s Disease

US Neurology ◽  
2010 ◽  
Vol 06 (01) ◽  
pp. 41
Author(s):  
Roy N Alcalay ◽  
Cheryl Waters ◽  
◽  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Family History ◽  
Early Onset ◽  
Late Onset ◽  
Positive Family History ◽  
Disease Onset ◽  
Leucine Rich Repeat ◽  
Strong Family History ◽  
Early Onset Parkinson’S Disease

Early-onset Parkinson’s disease (EOPD) is defined as disease onset before 40 or 50 years of age. The clinical characteristics of EOPD are very similar to those of late-onset PD, but dystonia is more often a presenting symptom, dementia is rare, and disease progression may be slower. Mutations in several genes have been described in cases with EOPD, often with strong family history, including mutations in α-synuclein (SNCA),DJ-1, PTEN-induced kinase-1 (PINK-1), andATP13A2. However, the most common mutations identified in EOPD are in Parkin (PRKN), leucine-rich repeat kinase 2 (LRRK2), and glucocerebrosidase (GBA). With the exception ofSNCAandATP13A2carriers, mutation carriers are often indistinguishable from non-carriers. Large series of EOPD cases that are not ascertained by family history estimate mutation frequency at 4–16%. Given that the frequency of positive family history is much higher, we believe that many genetic risk factors are yet to be discovered.

scholarly journals Cross-talk between LRRK2 and PKA: implication for Parkinson's disease?

2017 ◽  
Vol 45 (1) ◽  
pp. 261-267 ◽  
Author(s):  
Elisa Greggio ◽  
Luigi Bubacco ◽  
Isabella Russo
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Cross Talk ◽  
Brain Function ◽  
Neuronal Development ◽  
Autosomal Dominant ◽  
Leucine Rich Repeat ◽  
Glia Cells ◽  
Multiple Processes ◽  
Brain Homeostasis

Evidence indicates that leucine-rich repeat kinase 2 (LRRK2) controls multiple processes in neurons and glia cells. Deregulated LRRK2 activity due to gene mutation represents the most common cause of autosomal dominant Parkinson's disease (PD). Protein kinase A (PKA)-mediated signaling is a key regulator of brain function. PKA-dependent pathways play an important role in brain homeostasis, neuronal development, synaptic plasticity, control of microglia activation and inflammation. On the other hand, a decline of PKA signaling was shown to contribute to the progression of several neurodegenerative diseases, including PD. In this review, we will discuss the accumulating evidence linking PKA and LRRK2 in neuron and microglia functions, and offer an overview of the enigmatic cross-talk between these two kinases with molecular and cellular implications.

410: Autosomal dominant late-onset Parkinson’s disease due to a novel A1442P mutation in the LRRK2 gene

2008 ◽  
Vol 15 (3) ◽  
pp. 344-345
Author(s):  
Yue Huang ◽  
Glenda M. Halliday ◽  
Frank L. Mastaglia ◽  
Dominic B. Rowe ◽  
Carolyn M. Sue
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Autosomal Dominant ◽  
Late Onset ◽  
Lrrk2 Gene

scholarly journals Genetics and Epigenetics of Parkinson's Disease

2012 ◽  
Vol 2012 ◽  
pp. 1-12 ◽  
Author(s):  
Fabio Coppedè
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Small Rna ◽  
Autosomal Dominant ◽  
Disease Risk ◽  
Sufficient Evidence ◽  
Recent Application ◽  
Leucine Rich Repeat ◽  
Parkinsonian Syndromes ◽  
Genome Wide

In 1997 a mutation in thea-synuclein(SNCA) gene was associated with familial autosomal dominant Parkinson’s disease (PD). Since then, several loci (PARK1-15) and genes have been linked to familial forms of the disease. There is now sufficient evidence that six of the so far identified genes at PARK loci (a-synuclein, leucine-rich repeat kinase 2, parkin, PTEN-induced putative kinase 1, DJ-1, andATP13A2) cause inherited forms of typical PD or parkinsonian syndromes. Other genes at non-PARK loci (MAPT, SCA1, SCA2, spatacsin, POLG1) cause syndromes with parkinsonism as one of the symptoms. The majority of PD cases are however sporadic “idiopathic” forms, and the recent application of genome-wide screening revealed almost 20 genes that might contribute to disease risk. In addition, increasing evidence suggests that epigenetic mechanisms, such as DNA methylation, histone modifications, and small RNA-mediated mechanisms, could regulate the expression of PD-related genes.

CHCHD2 mutations in autosomal dominant late-onset Parkinson's disease: a genome-wide linkage and sequencing study

2015 ◽  
Vol 14 (3) ◽  
pp. 274-282 ◽  
Author(s):  
Manabu Funayama ◽  
Kenji Ohe ◽  
Taku Amo ◽  
Norihiko Furuya ◽  
Junji Yamaguchi ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Autosomal Dominant ◽  
Late Onset ◽  
Genome Wide ◽  
A Genome

scholarly journals Parkinson's Disease: Leucine-Rich Repeat Kinase 2 and Autophagy, Intimate Enemies

2012 ◽  
Vol 2012 ◽  
pp. 1-9 ◽  
Author(s):  
José M. Bravo-San Pedro ◽  
Rubén Gómez-Sánchez ◽  
Elisa Pizarro-Estrella ◽  
Mireia Niso-Santano ◽  
Rosa A. González-Polo ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Neurodegenerative Disorder ◽  
Late Onset ◽  
Clinical Syndrome ◽  
Leucine Rich Repeat ◽  
Disease Etiology ◽  
Clinical Appearance ◽  
A Cell ◽  
Genetic And Environmental Factors

Parkinson's disease is the second common neurodegenerative disorder, after Alzheimer's disease. It is a clinical syndrome characterized by loss of dopamine-generating cells in the substancia nigra, a region of the midbrain. The etiology of Parkinson's disease has long been through to involve both genetic and environmental factors. Mutations in the leucine-rich repeat kinase 2 gene cause late-onset Parkinson's disease with a clinical appearance indistinguishable from Parkinson's disease idiopathic. Autophagy is an intracellular catabolic mechanism whereby a cell recycles or degrades damage proteins and cytoplasmic organelles. This degradative process has been associated with cellular dysfunction in neurodegenerative processes including Parkinson's disease. We discuss the role of leucine-rich repeat kinase 2 in autophagy, and how the deregulations of this degradative mechanism in cells can be implicated in the Parkinson's disease etiology.

scholarly journals (D620N) VPS35 causes the impairment of Wnt/β-catenin signaling cascade and mitochondrial dysfunction in a PARK17 knockin mouse model

2020 ◽  
Vol 11 (11) ◽  
Author(s):  
Ching-Chi Chiu ◽  
Yi-Hsin Weng ◽  
Ying-Zu Huang ◽  
Rou-Shayn Chen ◽  
Yu-Chuan Liu ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Autosomal Dominant ◽  
Late Onset ◽  
Substantia Nigra Pars Compacta ◽  
Protein Levels ◽  
Abnormal Morphology ◽  
Vacuolar Protein ◽  
Knockin Mouse ◽  
Active Caspase

AbstractPatients with familial type 17 of Parkinson’s disease (PARK17) manifest autosomal dominant pattern and late-onset parkinsonian syndromes. Heterozygous (D620N) mutation of vacuolar protein sorting 35 (VPS35) is genetic cause of PARK17. We prepared heterozygous VPS35D620N/+ knockin mouse, which is an ideal animal model of (D620N) VPS35-induced autosomal dominant PARK17. Late-onset loss of substantia nigra pars compacta (SNpc) dopaminergic (DAergic) neurons and motor deficits of Parkinson’s disease were found in 16-month-old VPS35D620N/+ mice. Normal function of VPS35-containing retromer is needed for activity of Wnt/β-catenin cascade, which participates in protection and survival of SNpc DAergic neurons. It was hypothesized that (D620N) VPS35 mutation causes the malfunction of VPS35 and resulting impaired activity of Wnt/β-catenin pathway. Protein levels of Wnt1 and nuclear β-catenin were reduced in SN of 16-month-old VPS35D620N/+ knockin mice. Downregulated protein expression of survivin, which is a target gene of nuclear β-catenin, and upregulated protein levels of active caspase-8 and active caspase-9 were observed in SN of VPS35D620N/+ mice at age of 16 months. VPS35 is involved in controlling morphology and function of mitochondria. Impaired function of VPS35 caused by (D620N) mutation could lead to abnormal morphology and malfunction of mitochondria. A significant decrease in mitochondrial size and resulting mitochondrial fragmentation was found in tyrosine hydroxylase-positive and neuromelanin-positive SNpc DAergic neurons of 16-month-old VPS35D620N/+ mice. Mitochondrial complex I activity or complex IV activity was reduced in SN of 16-month-old VPS35D620N/+ mice. Increased level of mitochondrial ROS and oxidative stress were found in SN of 16-month-old VPS35D620N/+ mice. Levels of cytosolic cytochrome c and active caspase-3 were increased in SN of VPS35D620N/+ mice aged 16 months. Our results suggest that PARK17 mutant (D620N) VPS35 impairs activity of Wnt/β-catenin signaling pathway and causes abnormal morphology and dysfunction of mitochondria, which could lead to neurodegeneration of SNpc DAergic cells.

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