Overlapping genetic architecture between Parkinson disease and melanoma

Dube, Umber; Ibáñez, Laura; Budde, John; Benítez, Bruno A.; Davis, Albert A.; Harari, Oscar; Iles, Mark M.; Law, Matthew; Brown, Kevin M.; Cruchaga, Carlos

doi:10.1007/s00401-019-02110-z

Cited by 25 publications

(22 citation statements)

References 91 publications

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“…Two other studies implicated somatic Parkin mutations in melanoma predisposition and progression [46,47]. Recently, Dube and colleagues leveraged summary statistic datasets from several large genome wide association studies to demonstrate a significant genetic correlation, overlapping gene expression, and 7 potential gene mediators of the connection between PD and melanoma [48]. Systemic pigmentation may also explain part of the link between PD and melanoma.…”

Section: Neuropathymentioning

confidence: 99%

Parkinson's disease and skin

Niemann

Billnitzer

Jankovic

2021

Parkinsonism & Related Disorders

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Parkinson's disease is associated with a variety of dermatologic disorders and the study of skin may provide insights into pathophysiological mechanisms underlying this common neurodegenerative disorder. Skin disorders in patients with Parkinson's disease can be divided into two major groups: 1) non-iatrogenic disorders, including melanoma, seborrheic dermatitis, sweating disorders, bullous pemphigoid, and rosacea, and 2) iatrogenic disorders related either to systemic side effects of antiparkinsonian medications or to the delivery system of antiparkinsonian therapy, including primarily carbidopa/levodopa, rotigotine and other dopamine agonists, amantadine, catechol-O-methyl transferase inhibitors, subcutaneous apomorphine, levodopa/carbidopa intestinal gel, and deep brain stimulation. Recent advances in our understanding of the role of α-synuclein in peripheral tissues, including the skin, and research based on induced pluripotent stem cells derived from skin fibroblasts have made skin an important target for the study of Parkinson's disease pathogenesis, drug discovery, novel stem cell therapies, and diagnostics.

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Section: Neuropathymentioning

confidence: 99%

Parkinson's disease and skin

Niemann

Billnitzer

Jankovic

2021

Parkinsonism & Related Disorders

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“…Nevertheless, two lines of evidence suggest that embryonic DA2 neurons may be the precursors of SNc neurons in both species. First, the observation that DA2 neurons express several factors that are later found in the SNc, including Sox6 (Panman et al, 2014), ALDH1A1 (Galter et al, 2003), Rgs6 (Bifsha et al, 2014), and Lmo3 (Bifsha et al, 2017); and second, these genes have been associated to PD either by GWAS studies (SOX6, Dube et al, 2019), microarray data in PD post-mortem samples (LMO3, Briggs et al, 2015) or the presence of Parkinsonian symptoms in Rgs6 −/− mice (Luo et al, 2019). Ultimately, lineage tracing experiments using either human embryonic tissue or hES cells differentiated into midbrain cell types will be necessary to define the lineage relationship between embryonic and postnatal/adult human mDA neuron subtypes.…”

Section: Factors Expressed In Post-mitotic Mda Cell Typesmentioning

confidence: 99%

Midbrain Dopaminergic Neuron Development at the Single Cell Level: In vivo and in Stem Cells

Ásgrímsdóttir

Arenas

2020

Front. Cell Dev. Biol.

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Parkinson's disease (PD) is a progressive neurodegenerative disorder that predominantly affects dopaminergic (DA) neurons of the substantia nigra. Current treatment options for PD are symptomatic and typically involve the replacement of DA neurotransmission by DA drugs, which relieve the patients of some of their motor symptoms. However, by the time of diagnosis, patients have already lost about 70% of their substantia nigra DA neurons and these drugs offer only temporary relief. Therefore, cell replacement therapy has garnered much interest as a potential treatment option for PD. Early studies using human fetal tissue for transplantation in PD patients provided proof of principle for cell replacement therapy, but they also highlighted the ethical and practical difficulties associated with using human fetal tissue as a cell source. In recent years, advancements in stem cell research have made human pluripotent stem cells (hPSCs) an attractive source of material for cell replacement therapy. Studies on how DA neurons are specified and differentiated in the developing mouse midbrain have allowed us to recapitulate many of the positional and temporal cues needed to generate DA neurons in vitro. However, little is known about the developmental programs that govern human DA neuron development. With the advent of single-cell RNA sequencing (scRNA-seq) and bioinformatics, it has become possible to analyze precious human samples with unprecedented detail and extract valuable high-quality information from large data sets. This technology has allowed the systematic classification of cell types present in the human developing midbrain along with their gene expression patterns. By studying human development in such an unbiased manner, we can begin to elucidate human DA neuron development and determine how much it differs from our knowledge of the rodent brain. Importantly, this molecular description of the function of human cells has become and will increasingly be a reference to define, evaluate, and engineer cell types for PD cell replacement therapy and disease modeling.

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“…While it is premature to comment on the functional pathways highlighted in the 40+ PD and LOPD, many of the pathways pulled out in the EOPD analysis are of interest. Much research has investigated the proposed genetic link between PD, pigmentation (peripheral melanin and neuromelanin) and melanoma 26,27 , therefore the identified high burden of EOPD URVs in the MsigDB hallmark UV response pathway further highlights the link between PD and melanoma, and additionally implicates a role for pigmentation in disease pathology. The mitotic spindle pathway is associated with microtubule stabilization, a process known to be dysregulated in PD 28 .…”

Section: Discussionmentioning

confidence: 99%

Whole-exome analysis in Parkinson’s disease reveals a high burden of ultra rare variants in early onset cases

Bustos¹,

Krainc²,

Lubbe³

2020

Preprint

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Word count: Abstract = 208Main text = 4,362 (3,285 excluding Methods) ABSTRACTParkinson's disease (PD) is a complex neurodegenerative disorder with a strong genetic component. We performed a "hypothesis-free" exome-wide burden-based analysis of different variant frequencies, predicted functional impact and age of onset classes, in order to expand the understanding of rare variants in PD. Analyzing whole-exome data from a total of 1,425 PD cases and 596 controls, we found a significantly increased burden of ultra-rare (URV= private variants absent from gnomAD) protein altering variants (PAV) in early-onset PD cases (EOPD, <40 years old; P=3.95x10 -26 , beta=0.16, SE=0.02), compared to LOPD cases (>60 years old, late-onset), where more common PAVs (allele frequencies <0.001) showed the highest significance and effect (P=0.026, beta=0.15, SE=0.07). Gene-set burden analysis of URVs in EOPD highlighted significant disease-and tissue-relevant genes, pathways and protein-protein interaction networks that were different to that observed in non-EOPD cases. Heritability estimates revealed that URVs account for 15.9% of the genetic component in EOPD individuals. Our results suggest that URVs play a significant role in EOPD and that distinct etiological bases may exist for EOPD and sporadic PD. By providing new insights into the genetic architecture of PD, our study may inform approaches aimed at novel gene discovery and provide new directions for genetic risk assessment based on disease age of onset.

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Overlapping genetic architecture between Parkinson disease and melanoma

Cited by 25 publications

References 91 publications

Parkinson's disease and skin

Parkinson's disease and skin

Midbrain Dopaminergic Neuron Development at the Single Cell Level: In vivo and in Stem Cells

Whole-exome analysis in Parkinson’s disease reveals a high burden of ultra rare variants in early onset cases

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