Dataset Information

Role of LRRK2 variant p.Gly2019Ser in patients with Parkinsonism.

ABSTRACT:

Background & objectives

Parkinsonian disorder, including Parkinson's disease (PD), is an aetiologically complex neurodegenerative disorder. Mutations in leucine-rich repeat kinase 2 (LRRK2) gene have been implicated in an autosomal dominant form of PD with variable penetrance. The identification of a common LRRK2 variant (p.Gly2019Ser) in dementia with Lewy bodies indicated its potential role in Parkinsonian disorder. The current study was aimed to identify the p.Gly2019Ser variant in Indian patients with Parkinsonian disorder.

Methods

The patient group consisting of 412 classical PD patients, 107 PD patients with cognitive impairment, 107 patients with Parkinson plus syndrome and 200 unrelated controls were recruited from eastern part of India. The allele representing p.Gly2019Ser variant was screened by polymerase chain reaction followed by restriction fragment length polymorphism analysis.

Results

The p.Gly2019Ser variant was identified in an East Indian young-onset female PD patient in a heterozygous state having several motor and autonomic problems without disturbed cognition. Her younger brother, sister and elder son harbouring the same mutation were asymptomatic carriers for the variant. However, the influence of DNM3 on decreased disease onset in this family was not clear.

Interpretation & conclusions

Identification of the p.Gly2019Ser variant in only one patient among a large number of Indian patients (n=626) with Parkinsonian disorder in our study suggests a limited role of the LRRK2 variant towards disease pathogenesis.

SUBMITTER: Sadhukhan D

PROVIDER: S-EPMC7602925 | biostudies-literature | 2020 Jun

REPOSITORIES: biostudies-literature

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Publications

Role of <i>LRRK2</i> variant p.Gly2019Ser in patients with Parkinsonism.

Sadhukhan Dipanwita D Biswas Arindam A Bhaduri Arunima A Sarkar Neelanjana N Biswas Atanu A Das Shyamal K SK Banerjee Tapas K TK Ray Kunal K Ray Jharna J

The Indian journal of medical research 20200601 6

<h4>Background & objectives</h4>Parkinsonian disorder, including Parkinson's disease (PD), is an aetiologically complex neurodegenerative disorder. Mutations in leucine-rich repeat kinase 2 (LRRK2) gene have been implicated in an autosomal dominant form of PD with variable penetrance. The identification of a common LRRK2 variant (p.Gly2019Ser) in dementia with Lewy bodies indicated its potential role in Parkinsonian disorder. The current study was aimed to identify the p.Gly2019Ser variant in In ...[more]

PMID: 32719233

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Project description:BackgroundParkinson's disease (PD) is one of the most important neurodegenerative disorders in elderly people. Mutations in the leucine-rich repeat kinase 2 (LRRK2) gene are found in a large proportion of the patients with sporadic and familial PD. Mutations can occur at different locations in the LRRK2. Patients with LRRK2 ROC-COR mutations face an increased risk of typical motor symptoms of PD, along with cognitive decline. An animal model with a monogenic LRRK2 gene mutation is a suitable model for exploring the pathophysiology of PD and identifying potential drug therapies. However, the effect of homozygous (HOM) LRRK2 in PD pathophysiology is unclear.MethodsWe established human LRRK2 (hLRRK2) R1441G HOM transgenic (Tg) mice to explore the phenotype and pathological features that are associated with hLRRK2 R1441G Tg mouse models and discuss the potential clinical relevance. The open field test (OFT) was performed to examine motor and nonmotor behaviors. A CatWalk analysis system was used to study gait function. [18F]FDOPA PET was used to investigate functional changes in the nigrostriatal pathway in vivo. Transmission electron microscopy was used to examine the morphological changes in mitochondria and lysosomes in the substantia nigra.ResultsThe R1441G HOM Tg mice demonstrated gait disturbance and exhibited less anxiety-related behavior and exploratory behavior than mice with hLRRK2 at 12 months old. Additionally, [18F]FDOPA PET showed a reduction in FDOPA uptake in the striatum of the HOM Tg mice. Notably, there was significant lysosome and autophagosome accumulation in the cytoplasm of dopaminergic neurons in R1441G hemizygous (HEM) and HOM mice. Moreover, it was observed using transmission electron microscopy (TEM) that the mitochondria of R1441G Tg mice were smaller than those of hLRRK2 mice.ConclusionThis animal provides a novel HOM hLRRK2 R1441G Tg mouse model that reproduces some phenotype of Parkinsonism in terms of both motor and behavioral dysfunction. There is an increased level of mitochondrial fission and no change in the fusion process in the group of HOM hLRRK2 R1441G Tg mouse. This mutant animal model of PD might be used to study the mechanisms of mitochondrial dysfunction and explore potential new drug targets.