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Central nervous system: Adult-onset and psychiatric disorders
Published in Angus Clarke, Alex Murray, Julian Sampson, Harper's Practical Genetic Counselling, 2019
Most cases of Parkinson’s disease (PD) are primary rather than secondary to arteriosclerosis or encephalitis, and a prevalence of around 1 in 10,000 is seen in most European countries. PD onset is age related, affecting ∼1% of those at least 60 years old and becoming more prevalent with increasing age. Most cases are sporadic, or at least non-Mendelian, but a few large, early-onset (<50 years) dominant families have been recorded, and some of these have shown mutations in the gene encoding α-synuclein on chromosome 4q (SNCA). A less rare dominant form is caused by mutations in LRRK2, and several rare autosomal recessive genes have now also been implicated.
The nervous system
Published in Laurie K. McCorry, Martin M. Zdanowicz, Cynthia Y. Gonnella, Essentials of Human Physiology and Pathophysiology for Pharmacy and Allied Health, 2019
Laurie K. McCorry, Martin M. Zdanowicz, Cynthia Y. Gonnella
Although the exact etiology of Parkinson’s disease is still unknown, evidence suggests that certain genetic variations or environmental exposures may increase and individuals risk for developing Parkinson’s disease. It is likely that Parkinson’s disease develops as a result of complex interactions between genes and environmental factors. One potential causative gene mutation is found on chromosome 4 in a gene that codes for the protein α-synuclein, a major component of the abnormal accumulations called Lewy bodies that are found in the affected dopaminergic neurons of patients with Parkinson’s disease. Other gene mutations associated with Parkinson’s disease include those in LRRK2, PARK2, PARK7, PINK1, and SNCA genes. Environmental exposure to substances such as manganese (in welders) and pesticides as well as brain injury (boxers) have also been associated with an increased risk for the development of Parkinson’s disease
Preclinical Models
Published in George C. Kagadis, Nancy L. Ford, Dimitrios N. Karnabatidis, George K. Loudos, Handbook of Small Animal Imaging, 2018
Irene Cuadrado, Jesús Egido, Jose Luis Zamorano, Carlos Zaragoza
Models of Parkinson’s disease are based on single point mutations of the gene encoding for alpha-synuclein (Kahle et al. 2000), whereas overexpression of this protein in mice (Masliah and Hashimoto 2002) strongly resembles the Lewy bodies and neuritis of Parkinson’s and other neurodegenerative pathologies (Kirik and Bjorklund 2003). Alpha-synuclein models, as well as mutated forms of the LRRK2 gene (Lee et al. 2012), recapitulate most of the symptoms of human Parkinson’s disease, but the early dopaminergic neuronal loss in the substantia nigra, as early cause of disease, is still under investigation, and yet no models are available to reproduce this pathological condition.
Nutrigenomics in Parkinson’s disease: diversity of modulatory actions of polyphenols on epigenetic effects induced by toxins
Published in Nutritional Neuroscience, 2023
Moara Rodrigues-Costa, Matheus Santos de Sousa Fernandes, Gabriela Carvalho Jurema-Santos, Lílian Vanessa da Penha Gonçalves, Belmira Lara da Silveira Andrade-da-Costa
Another milestone in research into the genetic mechanisms of PD was the discovery of mutations in the leucine-rich repeat gene 2 (LRRK2) in families with autosomal-dominant parkinsonism.26,27 These mutations in the LRRK2 gene are associated with early and late-onset cases. This gene plays an important role in neuroinflammation and may also be involved in the deregulation of α-syn and microtubule-associated tau (MAPT) proteins.26–28 Heterozygous mutations in the GBA gene, which encodes the lysosomal enzyme b-glucocerebroside, are risk factors for the development of the more severe form of parkinsonism, usually characterized by early onset, rapid neurodegeneration, induced by higher levels of the α-syn protein, risks of cognitive deficits and dementia.29,30 Some studies have shown that polymorphisms in the MAPT gene are strongly associated with the development of dementia and that these variants may interact synergistically with polymorphisms of other genes, such as SNCA, thus contributing to the severity of the disease.31 Polymorphisms in the PARKIN (parkin RBR E3 ubiquitin protein ligase), PINK1 (PTEN-induced kinase 1) and DJ-1 (PARKIN7) genes, all of which play important roles in cellular and mitochondrial homeostasis, have been also reported and are considered to be the main causes for early-onset PD.30,32
The genetic background of Parkinson’s disease and novel therapeutic targets
Published in Expert Opinion on Therapeutic Targets, 2022
András Salamon, Dénes Zádori, László Szpisjak, Péter Klivényi, László Vécsei
The LRRK2 gene contains 51 exons, which encode a 2527 amino acid long protein [5]. The LRRK2 protein is a homodimer with GTPase and kinase functions, harboring the following domains: (1) protein-protein interaction domains: armadillo (ARM), ankyrin-like (ANK), leucine-rich repeat (LRR) and WD40; (2) serine-threonine kinase domain; (3) Ras of complex protein (Roc) – C-terminal of Roc (COR) tandem domain [10]. The vast majority of pathogenic mutations identified to date are located close to the carboxyl terminus of the protein [10]. The most frequent mutation is c.6055 G > A (p.G2019S) [10]. The penetrance of mutations in the LRRK2 gene is variable. The biological function of the LRRK2 protein is not yet known in detail, however, it may have an effect on cell signaling and subcellular transport processes [10].
Possible association between the lrrk2 gene and anxiety behavior: a systematic literature review
Published in Journal of Neurogenetics, 2022
RE Moreira-Júnior, RM Souza, JG de Carvalho, JP Bergamini, AL Brunialti-Godard
LRRK2 is a large multi-domain protein with two catalytic sites: a GTPase and a kinase connected by a catalytic site with multiple protein-protein interaction functions (Gilsbach & Kortholt, 2014). The biological role of LRRK2 is not yet fully understood, but there is evidence of its importance in many cellular functions, such as regulation of inflammation, cytoskeleton, vesicular trafficking, protein synthesis, and proteostasis (Esteves et al.,2014; Marchand et al.,2020). Mutations in LRRK2 are considered the most common cause of familial Parkinson’s disease, and variations in the gene also show an association with increased risk of sporadic Parkinson’s disease. Immune-related conditions, such as inflammatory bowel disease and leprosy, have also been linked to LRRK2 activity (Marchand et al.,2020; R.L. Wallings & Tansey, 2019). Interestingly, ADs are found in patients with Parkinson’s disease, inflammatory bowel disease, and leprosy (Byrne et al.,2017; Choi et al.,2019; Reynolds et al.,2020; Sanchez et al.,2021; Schrag & Taddei, 2017; Somar et al.,2020).