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

Parkinson’s disease (PD) is a heterogeneous neurodegenerative disease characterized by the progressive loss of dopaminergic neurons in the substantia nigra pars compacta and the widespread occurrence of proteinaceous inclusions known as Lewy bodies and Lewy neurites. The etiology of PD is still far from clear, but aging has been considered as the highest risk factor influencing the clinical presentations and the progression of PD. Accumulating evidence suggests that aging and PD induce common changes in multiple cellular functions, including redox imbalance, mitochondria dysfunction, and impaired proteostasis. Age-dependent deteriorations in cellular dysfunction may predispose individuals to PD, and cellular damages caused by genetic and/or environmental risk factors of PD may be exaggerated by aging. Mutations in the LRRK2 gene cause late-onset, autosomal dominant PD and comprise the most common genetic causes of both familial and sporadic PD. LRRK2-linked PD patients show clinical and pathological features indistinguishable from idiopathic PD patients. Here, we review cellular dysfunctions shared by aging and PD-associated LRRK2 mutations and discuss how the interplay between the two might play a role in PD pathologies.

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Frequency of the LRRK2 G2019S mutation in late-onset sporadic patients with Parkinson’s disease

Arquivos de Neuro-Psiquiatria ◽

10.1590/0004-282x20140019 ◽

2014 ◽

Vol 72 (5) ◽

pp. 356-359 ◽

Cited By ~ 6

Author(s):

Hsin Fen Chien ◽

Tamires Rocha Figueiredo ◽

Marianna Almeida Hollaender ◽

Fabiano Tofoli ◽

Leonel Takao Takada ◽

...

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Late Onset ◽

Small Sample Size ◽

Clinical Manifestations ◽

Small Sample ◽

Genetical Analysis ◽

G2019s Mutation ◽

Lrrk2 Gene ◽

And Gender

Mutations in the LRRK2 gene, predominantly G2019S, have been reported in individuals with autosomal dominant inheritance and sporadic Parkinson’s disease (PD). The G2019S mutation has an age-dependent penetrance and evidence shows common ancestry. The clinical manifestations are indistinguishable from idiopathic PD. Its prevalence varies according to the population studied ranging from less than 0.1% in Asians to 41% in North African Arabs. This study aimed to identify G2019S mutation in Brazilian idiopathic PD patients.Method:We sampled 100 PD patients and 100 age- and gender-matched controls. Genetical analysis was accomplished by polymerase chain reaction (PCR).Results:No G2019S mutations were found in both patients with sporadic PD and controls.Conclusions:Our results may be explained by the relatively small sample size.

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Neuronal hyperactivity in a LRRK2-G2019S cellular model of Parkinson's Disease

10.1101/2021.06.23.449591 ◽

2021 ◽

Author(s):

Edinson Lucumi Moreno ◽

Siham Hachi ◽

Sarah L Nickels ◽

Kalid IW Kane ◽

Masha Moein ◽

...

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Neuronal Activity ◽

Late Onset ◽

Induced Pluripotent Stem Cell ◽

Calcium Transient ◽

Lrrk2 Gene ◽

Lrrk2 G2019s ◽

Induced Pluripotent

Monogenic Parkinson's Disease can be caused by a mutation in the leucine-rich repeat kinase 2 (LRRK2) gene, causing a late-onset autosomal dominant inherited form of Parkinson's Disease. The function of the LRRK2 gene is incompletely understood, but several in vitro studies have reported that LRRK2-G2019S mutations affect neurite branching, calcium homeostasis and mitochondrial function, but thus far, there have been no reports of effects on electrophysiological activity. We assessed the neuronal activity of induced pluripotent stem cell derived neurons from Parkinson's Disease patients with LRRK2-G2019S mutations and isogenic controls. Neuronal activity of spontaneously firing neuronal populations was recorded with a fluorescent calcium-sensitive dye (Fluo-4) and analysed with a novel image analysis pipeline that combined semi-automated neuronal segmentation and quantification of calcium transient properties. Compared with controls, LRRK2-G2019S mutants have shortened inter-spike intervals and an increased rate of spontaneous calcium transient induction.

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Camptocormia and genetic Parkinson’s disease caused by the mutation of the LRRK2 gene. Case report.

10.5327/1516-3180.183 ◽

2021 ◽

Author(s):

Joseph Bruno Bidin Brooks ◽

Fábio César Prosdócimi ◽

Lara Fenley Granzotto ◽

Matheus Garcez Jorge Mariani

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Case Report ◽

Genetic Disease ◽

Late Onset ◽

Clinical Syndrome ◽

Muscle Stiffness ◽

Heterozygous Mutation ◽

Lrrk2 Gene ◽

Non Motor Symptoms

Context: Parkinsonism is a clinical syndrome characterized by bradykinesia, tremor at rest, muscle stiffness and postural instability. Parkinson’s disease is the most common cause of parkinsonism. Pathogenic mutations in the leucine- rich repeat kinase 2 gene (LRRK2) have been identified in PARK8-linked autosomal dominant parkinsonism. This mutation is the most common and explains about 1–7% of family cases of parkinsonism of European and American origin and 1–3% of sporadic PD. This case report was approved by the Ethics Committee of Universidade Metropolitana de Santos. Case Report: The present case relates to a 40-year-old, white man, who presented insidious and progressive parkinsonism for 6 years, akinetic-rigid and asymmetric (Hoehn Yahr 2.5 scale) associated with early camptocormia and non-motor symptoms and partial response to levodopa. The classic phenotype of late-onset parkinsonism was found on the paternal side of the patient’s family, suggesting family inheritance. Exome sequencing showed heterozygous mutation PARK8 LRRK2 (Gly2019Ser). Conclusions: The presentation of this case was aimed at alerting to Parkinson’s genetic disease in adults with family inheritance associated with early camptocormia. The presentation of this case was aimed at alerting to Parkinson’s genetic disease in adults with family inheritance associated with early camptocormia.

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

The Lancet Neurology ◽

10.1016/s1474-4422(14)70266-2 ◽

2015 ◽

Vol 14 (3) ◽

pp. 274-282 ◽

Cited By ~ 171

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

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Molecular analyses of the LRRK2 gene in European and North African autosomal dominant Parkinson's disease

Journal of Medical Genetics ◽

10.1136/jmg.2008.062612 ◽

2009 ◽

Vol 46 (7) ◽

pp. 458-464 ◽

Cited By ~ 41

Author(s):

S Lesage ◽

C Condroyer ◽

A Lannuzel ◽

E Lohmann ◽

A Troiano ◽

...

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Autosomal Dominant ◽

North African ◽

Molecular Analyses ◽

Lrrk2 Gene

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

Cell Death and Disease ◽

10.1038/s41419-020-03228-9 ◽

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

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.725348088.793533830 ◽

2017 ◽

Author(s):

Joseph Jankovic

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Autosomal Dominant ◽

Late Onset ◽

Genome Wide ◽

A Genome

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

Biochemical Journal ◽

10.1042/bj20150985 ◽

2016 ◽

Vol 473 (3) ◽

pp. 221-232 ◽

Cited By ~ 14

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.

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