Co-occurring WARS2 and CHRNA6 mutations in a child with a severe form of infantile parkinsonism

Martinelli, Simone; Cordeddu, Viviana; Galosi, Serena; Lanzo, Ambra; Palma, Eleonora; Pannone, Luca; Ciolfi, Andrea; Nottia, Michela Di; Rizza, Teresa; Bocchinfuso, Gianfranco; Traversa, Alice; Caputo, Viviana; Farrotti, Andrea; Carducci, Claudia; Bernardini, Laura; Cogo, Susanna; Paglione, Maria; Venditti, Martina; Bentivoglio, A.R.; Ng, Joanne; Kurian, Manju A.; Civiero, Laura; Greggio, Elisa; Stella, Lorenzo; Trettel, Flavia; Sciaccaluga, Miriam; Roseti, Cristina; Carrozzo, Rosalba; Fucile, Sergio; Limatola, Cristina; Schiavi, Elia Di; Tartaglia, Marco; Leuzzi, Vincenzo

doi:10.1016/j.parkreldis.2020.02.003

Cited by 18 publications

(24 citation statements)

References 10 publications

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“…GAD2 [156], TAC3 [157], NCR1 [158], IL7R [159], GATA3 [160], FCRL3 [161] and IL18R1 [162] have been reported as most promising biomarkers for early diagnosis and prognosis prediction of multiple sclerosis, but these genes might be novel target for AD. FLT3 [163], CHRNB4 [164], PAK1 [165], CHRNB3 [166], GRIN2A [167], CHRNA6 [168], PENK (proenkephalin) [169], CHRNB4 [170], IGF2 [171], TLR9 [172] and CACNG5 [173] were revealed to serve an important role in Parkinson’s disease, but these genes might be novel target for AD. The expression of SLC30A3 [174], NEFH (neurofilament heavy) [175], SYNGR4 [176], S100A4 [177], HSPB1 [178] and KIF5A [179] are associated with amyotrophic lateral sclerosis, but these genes might be novel target for AD.…”

Section: Discussionmentioning

confidence: 99%

Bioinformatics analyses of significant genes, related pathways and candidate prognostic biomarkers in Alzheimer’s disease

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Cm²

2021

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Alzheimers disease (AD) is one of the most common causes of dementia and frailty. This study aimed to use bioinformatics analysis to identify differentially expressed genes (DEGs) in AD. The Expression profiling by high throughput sequencing dataset GSE125583 was downloaded from the Gene Expression Omnibus (GEO) database and DEGs were identified. After assessment of Gene Ontology (GO) terms and pathway enrichment for DEGs, a protein protein interaction (PPI) network, module analysis, miRNA hub gene regulatory network construction and TF hub gene regulatory network were conducted via comprehensive target prediction and network analyses. Finally, we validated hub genes by receiver operating characteristic curve (ROC) and RT-PCR. In total, 956 DEGs were identified in the AD samples, including 479 up regulated genes and 477 down regulated genes. Functional enrichment analysis showed that these DEGs are mainly involved in the neuronal system, GPCR ligand binding, regulation of biological quality and cell communication. The hub genes of PAK1, ELAVL2, NSF, HTR2C, TERT, UBD, MKI67, HSPB1, PYHIN1 and TES might be associated with AD. The diagnostic value and expression levels of these hub genes in AD were further confirmed by ROC analysis and RT-PCR. In conclusion, we identified pathways and crucial candidate genes that affect the outcomes of patients with AD, and these genes might serve as potential therapeutic targets.

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Section: Discussionmentioning

confidence: 99%

Bioinformatics analyses of significant genes, related pathways and candidate prognostic biomarkers in Alzheimer’s disease

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Cm²

2021

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“…This mutation was identified as a genetic modifier that enhanced severity of infantile Parkinsonism and is likely to reduce activity of a DN-expressed nAChR. Importantly this mutation was also identified as an enhancer of the disease causing effects of a mutation in WARS2, mitochondrial tryptophanyl tRNA synthase, which was shown to reduce mitochondrial energy production (Martinelli et al, 2020).…”

Section: Involvement Of Protective Mitochondrial-dependent Pathways Imentioning

confidence: 99%

Conserved nicotine-activated neuroprotective pathways involve mitochondrial stress

Nourse

Harshefi

Marom

et al. 2020

Preprint

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Tobacco smoking is a risk factor for several human diseases. Conversely, smoking also reduces the prevalence of Parkinson's disease (PD), whose hallmark is degeneration of substantia nigra dopaminergic neurons (DNs). We use C. elegans as a model to investigate whether tobacco-derived nicotine activates nicotinic acetylcholine receptors (nAChRs) to selectively protect DNs. Using this model we demonstrate conserved functions of DNexpressed nAChRs. We find that DOP-2, a D3-receptor homolog, MCU-1, a mitochondrial calcium uniporter, and PINK-1, PTEN-induced kinase 1, are required for nicotine-mediated protection of DNs. Together, our results support involvement of calcium-dependent mitochondrial stress activation of PINK-1 in nicotine-dependent neuroprotection. This suggests that nicotine's selective protection of substantia nigra DNs is due to the confluence of two factors: first, their unique vulnerability to mitochondrial stress, which is mitigated by increased mitochondrial quality control due to PINK1 activation; and second, to their specific expression of D3 receptors.Epidemiological studies show that tobacco smoking reduces the prevalence of Parkinson's disease (PD) (Li et al., 2015). A hallmark of PD is degeneration of substantia nigra dopaminergic neurons (DNs). Effects of tobacco smoking on degeneration of these neurons may depend on tobacco-derived nicotine and on nicotinic acetylcholine receptors (nAChRs). Support for this hypothesis comes from several lines of evidence. These include: i)

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“…Caenorhabditis elegans is a nematode with a defined number of cells (959 somatic cells in the adult), among which 302 are neurons. It has proven to be a useful model organism for investigating molecular and cellular aspects of neuron development and neurodegeneration in numerous human diseases, including PD and other neurodegenerative conditions [91,92]. Moreover, the degeneration of specific neuronal populations, can be easily analyzed in living animals [93], thanks to their transparency and the expression of fluorescent proteins.…”

Section: Role Of Genetically Tractable Models In the Study Of Biologimentioning

confidence: 99%

Understanding the Effects of Deep Space Radiation on Nervous System: The Role of Genetically Tractable Experimental Models

2020

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Space agencies are working to establish a permanent human presence on the moon and to reach Mars within the next few decades. In these missions, astronaut crew members will be exposed to moderate doses of the highly energetic particles that compose galactic cosmic rays (GCR). GCR consist of alpha particles, protons, and high atomic number ions, stripped of their electrons (HZE), which are relatively rare, but are also highly ionizing. HZE are particularly damaging to biological tissues, because they can penetrate to much deeper layers of shielding materials than gamma rays and x-rays and produce within tissues long ionization tracks, with strongly clustered damage to information molecules. The consequences of such damage to central nervous system health is a major concern. A strong development of new knowledge and models, which may help to predict the risk of individual astronauts, is an absolute requirement in this field. Genetically tractable animal models offer unique opportunities to directly investigate the genetic and molecular events that may affect the biological response to GCR and related radiation.

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Co-occurring WARS2 and CHRNA6 mutations in a child with a severe form of infantile parkinsonism

Cited by 18 publications

References 10 publications

Bioinformatics analyses of significant genes, related pathways and candidate prognostic biomarkers in Alzheimer’s disease

Bioinformatics analyses of significant genes, related pathways and candidate prognostic biomarkers in Alzheimer’s disease

Conserved nicotine-activated neuroprotective pathways involve mitochondrial stress

Understanding the Effects of Deep Space Radiation on Nervous System: The Role of Genetically Tractable Experimental Models

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