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

Filippou, Panagiota; Outeiro, Tiago F.

doi:10.1002/mds.28425

Cited by 21 publications

(30 citation statements)

References 69 publications

(61 reference statements)

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“…The prevailing hypothesis 26,32‐34,37,39 to describe the inverse correlation between α‐syn expression and melanin production states that α‐syn disrupts the activities of catalytic enzymes involved in melanin biosynthesis, namely, tyrosine hydroxylase (TH) and tyrosinase (TYR), which is based on a few primary research studies 72,77,78 . In dopaminergic brain cells, α‐syn has been shown to coimmunoprecipitate with TH and negatively regulate its activity by activating protein phosphatase PP2A, the enzyme responsible for dephosphorylating and inactivating TH 77,78 .…”

Section: Current Hypothesesmentioning

confidence: 99%

“…Although the epidemiological link between PD and melanoma is now well established, fewer studies have investigated potential underlying genetic links. Recent review articles have discussed these potential genetic links 26,[32][33][34][35][36][37][38][39] ; however, we feel it is important to highlight a few articles here. Recently, a metaanalysis of four individual genome-wide association studies (one melanoma and three PD) was performed and found a positive genetic correlation between melanoma and PD, but not melanoma and other neurodegenerative disorders.…”

Section: Genetic Links Between Pd and Melanomamentioning

confidence: 99%

“…The prevailing hypothesis 26,[32][33][34]37,39 to describe the inverse correlation between α-syn expression and melanin production states that α-syn disrupts the activities of catalytic enzymes involved in melanin biosynthesis, namely, tyrosine hydroxylase (TH) and tyrosinase (TYR), which is based on a few primary research studies. 72,77,78 In dopaminergic brain cells, α-syn has been shown to coimmunoprecipitate with TH and negatively Although several studies have reported the endogenous expression of α-syn in melanoma cell lines, these two studies are highlighted because they compared α-syn expression between various cell lines under the same conditions.…”

Section: Current Hypotheses α-Syn Disrupts Tyrosine Hydroxylase And/or Tyrosinase Activitymentioning

confidence: 99%

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Linking Parkinson's Disease and Melanoma: Interplay Between α‐Synuclein and Pmel17 Amyloid Formation

Dean

Lee

2021

Movement Disorders

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A BS TRACT: Parkinson's disease (PD) is a neurodegenerative disorder associated with the death of dopaminergic neurons within the substantia nigra of the brain. Melanoma is a cancer of melanocytes, pigmented cells that give rise to skin tone, hair, and eye color. Although these two diseases fundamentally differ, with PD leading to cell degeneration and melanoma leading to cell proliferation, epidemiological evidence has revealed a reciprocal relationship where patients with PD are more susceptible to melanoma and patients with melanoma are more susceptible to PD. The hallmark pathology observed in PD brains is intracellular inclusions, of which the primary component is proteinaceous α-synuclein (α-syn) amyloid fibrils. α-Syn also has been detected in cultured melanoma cells and tissues derived from patients with melanoma, where an inverse correlation exists between α-syn expression and pigmentation. Although this has led to the prevailing hypothesis that α-syn inhibits enzymes involved in melanin biosynthesis, we recently reported an alternative hypothesis in which α-syn interacts with and modulates the aggregation of Pmel17, a functional amyloid that serves as a scaffold for melanin biosynthesis. In this perspective, we review the literature describing the epidemiological and molecular connections between PD and melanoma, presenting both the prevailing hypothesis and our amyloid-centric hypothesis. We offer our views of the essential questions that remain unanswered to motivate future investigations. Understanding the behavior of α-syn in melanoma could not only provide novel approaches for treating melanoma but also could reveal insights into the role of α-syn in PD.

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Section: Current Hypothesesmentioning

confidence: 99%

Section: Genetic Links Between Pd and Melanomamentioning

confidence: 99%

Section: Current Hypotheses α-Syn Disrupts Tyrosine Hydroxylase And/or Tyrosinase Activitymentioning

confidence: 99%

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Linking Parkinson's Disease and Melanoma: Interplay Between α‐Synuclein and Pmel17 Amyloid Formation

Dean

Lee

2021

Movement Disorders

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“…Interestingly, α-synuclein is overexpressed in melanoma and other cancers. On the other hand, genes primarily implicated in cancer-related pathways, such as TP53 , MTOR , TSC1/2 , PIN1 , MC1R and the PTEN pathways, have also been shown to be implicated in PD pathogenesis [ 16 ]. Thus, increasing evidence points to the disruption of common cellular events in both cancer and PD [ 2 , 3 , 4 , 5 ], but the mechanisms underlying these associations require further studies.…”

Section: Introductionmentioning

confidence: 99%

A Computational Analysis in a Cohort of Parkinson’s Disease Patients and Clock-Modified Colorectal Cancer Cells Reveals Common Expression Alterations in Clock-Regulated Genes

Yalçin

Malhan

Basti

et al. 2021

Cancers

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Increasing evidence suggests a role for circadian dysregulation in prompting disease-related phenotypes in mammals. Cancer and neurodegenerative disorders are two aging related diseases reported to be associated with circadian disruption. In this study, we investigated a possible effect of circadian disruption in Parkinson’s disease (PD) and colorectal cancer (CRC). We used high-throughput data sets retrieved from whole blood of idiopathic PD (IPD) patients and time course data sets derived from an in vitro model of CRC including the wildtype and three core-clock knockout (KO) cell lines. Several gene expression alterations in IPD patients resembled the expression profiles in the core-clock KO cells. These include expression changes in DBP, GBA, TEF, SNCA, SERPINA1 and TGFB1. Notably, our results pointed to alterations in the core-clock network in IPD patients when compared to healthy controls and revealed variations in the expression profile of PD-associated genes (e.g., HRAS and GBA) upon disruption of the core-clock genes. Our study characterizes changes at the transcriptomic level following circadian clock disruption on common cellular pathways associated with cancer and neurodegeneration (e.g., immune system, energy metabolism and RNA processing), and it points to a significant influence on the overall survival of colon cancer patients for several genes resulting from our analysis (e.g., TUBB6, PAK6, SLC11A1).

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“…This leads to a loss of dopaminergic neurons within the substantia nigra pars compacta, depletion of dopamine in the striatum, and the presence of Lewy bodies ( Jankovic, 2008 ). In contrast to the excessive neuronal cell death observed in PD, cancer develops from unrestricted cell proliferation and resistance to cell death ( Filippou and Outeiro, 2021 ). Interestingly, with the development of a more comprehensive understanding of both diseases, an intimate link between PD and lung cancer has been gradually revealed.…”

Section: Introductionmentioning

confidence: 99%

Significance of Parkinson Family Genes in the Prognosis and Treatment Outcome Prediction for Lung Adenocarcinoma

Xiao

Zhang

et al. 2021

Front. Mol. Biosci.

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Epidemiological investigations have shown that patients with Parkinson’s disease (PD) have a lower probability of developing lung cancer. Subsequent research revealed that PD and lung cancer share specific genetic alterations. Therefore, the utilisation of PD biomarkers and therapeutic targets may improve lung adenocarcinoma (LUAD) diagnosis and treatment. We aimed to identify a gene-based signature from 25 Parkinson family genes for LUAD prognosis and treatment choice. We analysed Parkinson family gene expression and protein levels in LUAD, utilising multiple databases. Least absolute shrinkage and selection operator (LASSO) regression was used to construct a prognostic model based on the TCGA-LUAD cohort. We validated the model in external GEO cohorts. Immune cell infiltration was compared between risk groups, and GEO data was used to explore the model’s predictive ability for LUAD treatment response. Nearly all Parkinson family genes exhibited significant differential expression between LUAD and normal tissues. LASSO regression confirmed that our seven Parkinson family gene-based signature had excellent prognostic performance for LUAD, as validated in three GEO cohorts. The high-risk group was clearly associated with low tumour immune cell infiltration, suggesting that immunotherapy may not be an optimal treatment choice. This is the first Parkinson family gene-based model for the prediction of LUAD prognosis and treatment outcome. The association of these genes with poor prognosis and low immune infiltration requires further investigation.

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

Cited by 21 publications

References 69 publications

Linking Parkinson's Disease and Melanoma: Interplay Between α‐Synuclein and Pmel17 Amyloid Formation

Linking Parkinson's Disease and Melanoma: Interplay Between α‐Synuclein and Pmel17 Amyloid Formation

A Computational Analysis in a Cohort of Parkinson’s Disease Patients and Clock-Modified Colorectal Cancer Cells Reveals Common Expression Alterations in Clock-Regulated Genes

Significance of Parkinson Family Genes in the Prognosis and Treatment Outcome Prediction for Lung Adenocarcinoma

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