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Abstract
Nearly 200 years ago Parkinson’s disease (PD) was first described by James Parkinson as „shaking palsy“ . Up to the present the knowledge of this neurodegenerative disease has grown continuously. Most of the time PD begins at an age around 60 years or higher, but some patients show the first symptoms already younger. The patients with an age at onset under 50 years are defined by the term „early-onset parkinson disease“ (EOPD) . Although the exact pathomechanisms are still unknown, a rash of biochemical processes are well researched in the past studies. Main components are inflammation , oxidative stress , protein aggregation and high brain iron accumulation . All these processes can promote or trigger each other. However, the exact etiology of Parkinson's disease and the subtypes like EOPD are still unexplained. Since the first detection of a triggering gene in the etiology of Parkinson 's disease (α-Synuclein Gen, PARK1) (Polymeropoulos et al., 1997), twenty-three genes (PARK 1 – 23) with different significance for the disease have been identified in recent decades.
In 2006, the working group around Morgan et al. was able to detect mutations in the PLA2G6 gene in patients with neurodegeneration with brain iron accumulation (NBIA) and INAD (infantile neuroaxonal dystrophy). As with EOPD patients, the patients of the diseases show an early onset of symptoms and an increased iron content in the brain could be detected .
On this account, we considered PLA2G6 a candidate gene for EOPD and analyzed a cohort of altogether 268 PD patients with early onset, comparing them to a total of 257 healthy controls.
In a first group of 102 EOPD patients we identified a total of 10 polymorphisms in the exons of the gene. Four of the found SNPs were examined in a second group of 166 patients with EOPD. This led to the identification of another polymorphism in the exon 17 of the gene. Overall, the two heterozygous mutations 2339A> G (n = 2) and 2341G> A (n = 1) were detected in 3 (1.12%) patients with EOPD. None of the 257 healthy controls showed these polymorphisms. The two missense mutations are located on exon 17 in immediate vicinity to each other and lead to the exchange of asparagine to serine (2339A> G; N780S) and alanine to threonine (2341G> A, A781T) in the protein sequence. Thus, both are located in the c - terminal part of the gene in which different catalytic centers of the Phospholipase A2 have been detected . In 2009, Paisan-Ruiz demonstrated the PLA2G6 gene as a locus for patients with early-onset Parkinsonism (Paisan-Ruiz et al., 2009). Other studies published after this and our publication have also shown interesting mutations in the PLA2G6 gene in patients with EOPD, PD or other neurodegenerative diseases .
In summary, we could not demonstrate a large or even monogenetic significance of the PLA2G6 gene in EOPD. Nonetheless summarizing our results and current research, we consider the PLA2G6 gene a probable susceptibility gene with an impact in the etiology of EOPD. Although this seems to be the case for only a small amount of patients with EOPD, the PLA2G6 gene probably plays a significant role in the pathology of neurodegenerative diseases. Therefore, further investigations of the PLA2G6 gene in EOPD patients are necessary in further works.
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Created: 2021Issued: 2021-08-19Updated: 2021-08-19
Faculty
Medizin
Publisher
Philipps-Universität Marburg
Language
ger
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DoctoralThesis
DFG-subjects
ParkinsonPLA2G6 GenPhospholipase A2iPLA2NeurodegenerationEOPDfrüher Krankheitsbeginn
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610
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Kauther, Kai Michael: Das PLA2G6 Gen bei Parkinson Patienten mit frühem Krankheitsbeginn. : Philipps-Universität Marburg 2021-08-19. DOI: https://doi.org/10.17192/z2021.0306.
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This item has been published with the following license: In Copyright