Association Between Parkinson’s Disease and Melanoma: Putting the Pieces Together

Ye, Qing; Wen, Ya; Al-Kuwari, Nasser; Chen, Xiqun

doi:10.3389/fnagi.2020.00060

Cited by 34 publications

(34 citation statements)

References 132 publications

(137 reference statements)

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“…Microglial activation contributes to neurodegeneration in Parkinson's disease [47]. Interestingly, Parkinson's disease and melanoma are positively linked epidemiologically [48]. and MAP2+ cell counting in neurons treated with conditioned medium from primary microglia transduced with lentiviral BRAF vectors with and without siRNA transfection.…”

Section: Discussionmentioning

confidence: 99%

Oncogenic BRAF V600E induces glial proliferation through ERK and neuronal death through JNK

Al-Kuwari

Srivast

et al. 2021

Preprint

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Background: Activating V600E in BRAF is a common driver mutation in cancers of multiple tissue origins, including melanoma and glioma. BRAF V600E has also been implicated in neurodegeneration. The present study aims to characterize BRAF V600E on cell death and survival in three major cell types of the CNS: neurons, astrocytes, and microglia. Methods : Multiple primary cultures and cell lines of glial cells and neurons were employed. BRAF V600E as well as BRAF WT expression was mediated by lentivirus or retrovirus. Blockage of downstream effectors were achieved by siRNA. Gene expression data from patients with Parkinson’s disease was analyzed. Results : In astrocytes and microglia, BRAF V600E induces cell proliferation, and the proliferative effect in microglia is mediated by activated ERK but not JNK. Conditioned medium from BRAF V600E -expressing microglia induced neuronal cell death. In neuronal cells, BRAF V600E directly induces cell death, through JNK but not ERK. We further show that BRAF-related genes are enriched in pathways in patients with Parkinson’s disease. Conclusions : Our study identifies distinct consequences mediated by distinct downstream effectors in dividing glial cells and in neurons following the same BRAF mutational activation and a causal link between BRAF-activated microglia and neuronal cell death that does not require physical proximity. It provides insight into a possibly important role of BRAF in neurodegeneration as a result of either dysregulated BRAF in neurons or its impact on glial cells.

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Section: Discussionmentioning

confidence: 99%

Oncogenic BRAF V600E induces glial proliferation through ERK and neuronal death through JNK

Al-Kuwari

Srivast

et al. 2021

Preprint

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“…Modulation of LAMP2A expression and consecutive CMA activity is regarded as a therapeutic target for PD and other synucleinopathies [ 199 ]. Of note, increased exosomal miRNA-21 signaling is a common feature of malignant melanoma and glioblastoma multiforme [ 200 , 201 ], malignancies that exhibit higher rates of occurrence in patients with PD [ 202 , 203 ].…”

Section: Autophagy-lysosome Pathway Controls Exosomal α mentioning

confidence: 99%

Synergistic Effects of Milk-Derived Exosomes and Galactose on α-Synuclein Pathology in Parkinson’s Disease and Type 2 Diabetes Mellitus

Melnik

2021

IJMS

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Epidemiological studies associate milk consumption with an increased risk of Parkinson’s disease (PD) and type 2 diabetes mellitus (T2D). PD is an α-synucleinopathy associated with mitochondrial dysfunction, oxidative stress, deficient lysosomal clearance of α-synuclein (α-syn) and aggregation of misfolded α-syn. In T2D, α-syn promotes co-aggregation with islet amyloid polypeptide in pancreatic β-cells. Prion-like vagal nerve-mediated propagation of exosomal α-syn from the gut to the brain and pancreatic islets apparently link both pathologies. Exosomes are critical transmitters of α-syn from cell to cell especially under conditions of compromised autophagy. This review provides translational evidence that milk exosomes (MEX) disturb α-syn homeostasis. MEX are taken up by intestinal epithelial cells and accumulate in the brain after oral administration to mice. The potential uptake of MEX miRNA-148a and miRNA-21 by enteroendocrine cells in the gut, dopaminergic neurons in substantia nigra and pancreatic β-cells may enhance miRNA-148a/DNMT1-dependent overexpression of α-syn and impair miRNA-148a/PPARGC1A- and miRNA-21/LAMP2A-dependent autophagy driving both diseases. MiRNA-148a- and galactose-induced mitochondrial oxidative stress activate c-Abl-mediated aggregation of α-syn which is exported by exosome release. Via the vagal nerve and/or systemic exosomes, toxic α-syn may spread to dopaminergic neurons and pancreatic β-cells linking the pathogenesis of PD and T2D.

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“…Strikingly, melanoma is more frequent in PD patients, and PD is also more frequent in melanoma patients 6‐9 . Different hypotheses have been proposed to explain the co‐occurrence of both diseases, 10,11 but the underlying mechanisms still remain unknown. Both PD and melanoma are complex, multifaceted disorders, involving genetic and environmental risk factors 10 .…”

Section: An Intriguing Exception: the Association Between Pd And Melamentioning

confidence: 99%

“…Different hypotheses have been proposed to explain the co‐occurrence of both diseases, 10,11 but the underlying mechanisms still remain unknown. Both PD and melanoma are complex, multifaceted disorders, involving genetic and environmental risk factors 10 . Although a clear biological explanation for this epidemiological observation is lacking, the identification of possible mechanisms involved in the association between PD and melanoma 9 is of great interest.…”

Section: An Intriguing Exception: the Association Between Pd And Melamentioning

confidence: 99%

“…Although a clear biological explanation for this epidemiological observation is lacking, the identification of possible mechanisms involved in the association between PD and melanoma 9 is of great interest. Interestingly, the interplay between PD and melanoma has also been attributed to alterations in melanin and/or melanin biosynthetic enzymes 6,10 …”

Section: An Intriguing Exception: the Association Between Pd And Melamentioning

confidence: 99%

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Cancer and Parkinson's Disease: Common Targets, Emerging Hopes

Filippou

Outeiro

2020

Movement Disorders

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Cancer and neurodegeneration are two major leading causes of morbidity and death worldwide. At first sight, the two fields do not seem to share much in common and, if anything, might be placed on opposite ends of a spectrum. Although neurodegeneration results in excessive neuronal cell death, cancer emerges from increased proliferation and resistance to cell death. Therefore, one might expect significant differences in the underlying pathophysiological mechanisms. However, the more we deepen our understanding of these two types of diseases, the more we appreciate the unexpected overlap between them. Although most epidemiological studies support an inverse association between the risk for development of neurodegenerative diseases and cancer, increasing evidence points to a positive correlation between specific types of cancer, like melanoma, and neurodegenerative diseases, like Parkinson's disease (PD). We believe that deciphering the molecular processes and pathways underlying one of these diseases may significantly increase our understanding about the other. Therefore, the identification of novel biomarkers and therapeutic approaches in cancer, may lead to improved diagnosis and treatment of neurodegeneration, and vice versa. In this Viewpoint, we summarize recent findings connecting both diseases and speculate that insights from one disease may inform on mechanisms, and help identify novel biomarkers and targets for intervention, possibly leading to improved management of both diseases. © 2020 International Parkinson and Movement Disorder Society

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Association Between Parkinson’s Disease and Melanoma: Putting the Pieces Together

Cited by 34 publications

References 132 publications

Oncogenic BRAF V600E induces glial proliferation through ERK and neuronal death through JNK

Oncogenic BRAF V600E induces glial proliferation through ERK and neuronal death through JNK

Synergistic Effects of Milk-Derived Exosomes and Galactose on α-Synuclein Pathology in Parkinson’s Disease and Type 2 Diabetes Mellitus

Cancer and Parkinson's Disease: Common Targets, Emerging Hopes

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