Late-onset Parkinson's disease - Causes, Symptoms, and Genetic Analysis

Surname 1 Name: Course: Professor’s Name: Name of the school: Date: Late -onset Parkinson's disease Introduction Following Alzheimer in the list of most common neurodegenerative diseases is Parkinson's disease as the second most common (Schapira) . Parkinsons disease (PD) was named after James Parkinson, who first described the disease in 1817. It has an estimated prevalence of 150/100,000 , affecting about 1% of the population aged 60 years and above . Above eighty years, this percentage increases to 3% (Nussbaum and E llis) . Studies show that Asians and Africans have decreased risk of developing PD compared to the Hispanic and Caucasian race because of the increased levels of neuromelanin, a neuroprotective agent, in the substantia nigra associated with darker skin tones . Sex is also another factor affecting the epidemiology of PD, with more males affected than female s. Estrogen is believed to have neuroprotective activity in the brain. (Ball et al.) PD has multifactorial etiologies , an i nterplay of genetics and environmental factors , thus the sporadic and familial forms of PD. The final common pathway of this interplay i n the disease process of PD is the loss of substantial nigral dopaminergic neurons and the formation of Lewy bodies in the remnant neurons . Environmental neurotoxins such as illegal substances, heavy metals and pesticides can selectively damage the neurons in the substantia nigra. (Ball et al.) Genetics account for about 15% of familial PD. The Mendelian Surname 1 inheritance gives rise to two subsets of PD. One subtype is the essential tremor -related parkinsonism with autosomal dominance inheritance, and the other is the akinetic -rigid syndrome with autosomal recessive inheritance (Barbeau and Roy ) This study focuses on the late -onset PD entry number# 168600 according to the Online mendelian inheritance in man database. The disease has a multifactorial autosomal dominance inheritance. The clinical picture of late -onset PD is mainly characterized by neurological signs such as dystonia, dysarthria, shuffling gait and bradykinesia, rigidity and resting tremor, dementia, depression and sleep disturbances. Other features are the expressionless and masked face , constipation and urine urgency. The pathological picture shows the loss of dopaminergic neurons and Lewy bodies inclusions in the remaining neurons. Through genetic analysis , several gene loci associated w ith autosomal dominant PD , namely PARK , have been identified; however, most of these loci refer to clinical parkinsonisms instead of the idiopathic PD (Hardy et al.) Polymor phism of different genes, namely MAPT, GBA, GLUD2 , ADH1C and genes, has been associated with late -onset P D. Other gene mutations, especially those causing spinocerebellar ataxia, including ATXN3, TBP, ATXNOS and ATXN2, can increase the susceptibility of developing PD. Results The following image 1.1 shows the phenotype -gene relationship of late -onset PD ("OMIM Entry - # 168600 - PARKINSON DISEASE, LATE -ONSET; PD") Surname 1 Image 1.2 below shows an excel table pf phenotypic series PS168600 ("OMIM Entry - # 168600 - PARKINSON DISEASE, LATE -ONSET; PD") Surname 1 The following image 1. 3 shows the gene - phenotype relationship of GBA gene. ("OMIM Entry - * 606463 - GLUCOSIDASE, BETA, ACID; GBA") Image 1 .4 below shows the protein profile of the GBA gene derived from NCBI ("35 Selected Items - Protein - NCBI") Surname 1 The following image 1.4 shows the BLAST result of th e nucleotide sequence of the GBA gene in mouse and human acce ssion number NC_000069.7 and NC_000001.11, respectively. Surname 1 Discussion The glucosidase beta acid gene (GBA) The cytogenetic location of GBA is 1q22.On the same chromosome, 1,16 kb downstream from 1q22 is a pseudogene, and it is 2kb shorter than the GBA gene. The pseudogene is 96% similar to the functional gene, and its promoter is active when attached to a repor ter gene (Horowitz et al.) The NCBI protein profile of GBA shows different isoforms with a varying number of amino acids; this is due to variant mRNAs from alternative splicing of the gene ("35 Selected Items - Protein - NCBI") . The gene is also present in mouse; however, it is located on chromosome 3 and lacks the pseudogene. Pairwise Blasting of the nucleotide sequence of the GBA gene in mouse and humans shows a per cent identity of 80.49%. GBA is a protein -coding gene that encodes for an enzyme in the lys osome that catalyzes the cleavage of glycolipid glucosylceramide to glucose and ceramide. Almost 200 GBA gene mutations have been associated with Gaucher's disease, a lysosomal storage disease (Jmoudiak and Futerman) . Mutation in this gene leads to the for mation of glucocerebrosidase enzyme variants which are retained and degraded in the endoplasmic reticulum proteasome. Deficiency of the glucocerebrosidase leads to accumulation of substrate in the reticuloendothelial system . The GBA mutation is also associated with increased susceptibility of developing late - onset PD and Lewy body dementia . Several pathways have been formulated explaining how mutation of the GBA gene leads to the risk of development of PD . One of the pathways involves inhibition of au tophagy of alpha -synuclein in neurones. Hence, its accumulation and loss of the neuronesThe inhibition of autophagy can be either downregulation of the BECNI component or inactivation of the protein phosphatase 2A as a result of decreased activity of the glucocerebrosidase enzyme (Du et al.) The other pathway explains the Surname 1 concurrence of PD and Gaucher’s disease. PARK2 gene encodes for parkin, an E3 ubiquitin ligase functioning in the endoplasmic reticulum degradation proteasome to degrade the mutant glucoc erebrosidase (GCase). Accumulation of GCase variants upregulates parkin and eventual loss of function, leading to accumulation of parkin substrates which damages the dopaminergic neurons in PD (Ron et al.) . Microtubule -associated protein tau (MAPT) gene MAPT cytogenetic location is 17q21.31 , and it encodes for Microtubule -associated protein tau. MAPT mRNA transcripts derived from alternative splicing are expressed in different neurons based on the maturation stage and type of neuron. Mutation of MAPT gene is associated with dementia frontotemporal with parkinsonism. The tau haplotype (H1)is implicated in PD whereby the H1/H1 genotype increases the risk of developing PD by increasing alpha -synuclein fibrillization in individuals with lower alpha -synuclein concentration due to other genotypes apart from the Rep1 261/261. (Huang et al.) Ataxin 2(ATXN2) Ataxin 2 is one of the group of genes implicated in diseases caused by the expansion of microsatellite. The N - terminal of the protein encoded by this gene has a polyglutamine tract consisting of 14 -31 residues prone to expansion in a diseased state. Long expansion ranges of tract cause spinocerebellar ataxia 2 .Ind ividuals with trinucleotide repeats expansion in this gene show decreased dopamine in the nigrostriatal tract confirming the involvement of ataxin 2 mutation in PD. (Shan et al.) Glutamate decarboxylase 2 (GLUD 2) gene It encodes for a mitochondrial pro tein responsible for catalyzing the oxidative deamination of glutamate. Partial loss of this enzyme is associated with several neurodegenerative diseases. A rare GLUD 2 variant resulting from polymorphism of the Surname 1 regulator region of hGDH2expressed in the br ain causes early onset of PD. This variant is X-linked and accelerates the onset of PD by the destruction of neurons in the nigrostriatal pathway through increased glutamate oxidative dehydrogenation in hemizygous individuals. (Plaitakis et al.) Conclusion Genetic analysis of the GBA gene has led to the development of improved approaches to the treatment of PD. Potential gene therapy associated with mutated GBA gene in PD has been developed though it is yet to move into clinical trials (Alejandra V iviescas) . Most genes implicated in PD are associated with other neurogenerative disorders, for instance, the GBA gene in Gaucher's diseases and PD. Prevalence of PD is continuously increasing due to the prolonged life of the patients, most patients living for about ten to twenty years after diagnosis. (Topics et al.) Surname 1 References Nussbaum,, Robert L, and Christopher E. . Ellis. "Alzheimer's Disease And Parkinson's Disease | NEJM". New England Journal Of Medicine , 2021, https://www.nejm.org/doi/full/10.1056/NEJM2003ra020003. "OMIM Entry - # 168600 - PARKINSON DISEASE, LATE -ONSET; PD". Omim.Org , 2021, https://www.omim.org/entry/168600#title. "35 Selected Items - Protein - NCBI". Ncbi.Nlm.Nih.Gov , 2021, https://www.ncbi.nlm .nih.gov/protein/54607043,54607045,54607047,55584151,158257 254,284807152,221043110,221043360,119573485,119573486,119573487,119573488,2 21043580,13097171,2564914,284807150,658508440,1233272219,189065565,553300,2 21043376,658508445,183008,658508452,183012,2210 42442,183018,183017,183022,1 83026,183024,496369,183028,221043856,221043794. Alejandra Viviescas, PhD. "Potential One -Time Gene Therapy For Parkinson’S Linked To GBA...". Parkinson's News Today , 2021, https://parkinsonsnewstoday.com/2019/06/11/pr001 -possibl e-gene -therapy -for - parkinsons -with -gba -mutations -to-enter -clinical -trial/. Ball, Nicole et al. Parkinson's Disease And The Environment . 2021. Barbeau, André, and Madeleine Roy. "Familial Subsets In Idiopathic Parkinson’S Disease". Canadian Journal Of Neuro logical Sciences / Journal Canadien Des Sciences Neurologiques , vol 11, no. S1, 1984, pp. 144 -150. 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