Abstract
Parkinson's disease (PD) patients have higher rates of melanoma and vice versa, observations suggesting that the two conditions may share common pathogenic pathways. β-Catenin is a transcriptional cofactor that, when concentrated in the nucleus, upregulates the expression of canonical Wnt target genes, such as Nurr1, many of which are important for neuronal survival. β-Catenin-mediated activity is decreased in sporadic PD as well as in leucine-rich repeat kinase 2 (LRRK2) and β-glucosidase (GBA) mutation cellular models of PD, which is the most common genetic cause of and risk for PD, respectively. In addition, β-catenin expression is significantly decreased in more aggressive and metastatic melanoma. Multiple observational studies have shown smokers to have significantly lower rates of PD as well as melanoma implying that tobacco may contain one or more elements that protect against both conditions. In support, smoker's brains have significantly reduced levels of α-synuclein, a pathological intracellular protein found in PD brain and melanoma cells. Tobacco contains very high lithium levels compared to other plants. Lithium has a broad array of neuroprotective actions, including enhancing autophagy and reducing intracellular α-synuclein levels, and is effective in both neurotoxin and transgenic preclinical PD models. One of lithium's neuroprotective actions is enhancement of β-catenin-mediated activity leading to increased Nurr1 expression through its ability to inhibit glycogen synthase kinase-3 β (GSK-3β). Lithium also has anti-proliferative effects on melanoma cells and the clinical use of lithium is associated with a reduced incidence of melanoma as well as reduced melanoma-associated mortality. This is the first known report hypothesizing that inhaled lithium from smoking may account for the associated reduced rates of both PD and melanoma and that this protection may be mediated, in part, through lithium-induced GSK-3β inhibition and consequent enhanced β-catenin-mediated activity. This hypothesis could be directly tested in clinical trials assessing lithium therapy's ability to affect β-catenin-mediated activity and slow disease progression in patients with PD or melanoma.
TY - JOUR
T1 - High lithium levels in tobacco may account for reduced incidences of both Parkinson's disease and melanoma in smokers through enhanced β-catenin-mediated activity.
A1 - Guttuso,Thomas,Jr
Y1 - 2019/07/04/
PY - 2019/04/27/received
PY - 2019/07/03/accepted
PY - 2019/8/25/entrez
PY - 2019/8/25/pubmed
PY - 2020/2/25/medline
KW - Epidemiology
KW - Lithium
KW - Melanoma
KW - Parkinson's disease
KW - Smoking
SP - 109302
EP - 109302
JF - Medical hypotheses
JO - Med Hypotheses
VL - 131
N2 - Parkinson's disease (PD) patients have higher rates of melanoma and vice versa, observations suggesting that the two conditions may share common pathogenic pathways. β-Catenin is a transcriptional cofactor that, when concentrated in the nucleus, upregulates the expression of canonical Wnt target genes, such as Nurr1, many of which are important for neuronal survival. β-Catenin-mediated activity is decreased in sporadic PD as well as in leucine-rich repeat kinase 2 (LRRK2) and β-glucosidase (GBA) mutation cellular models of PD, which is the most common genetic cause of and risk for PD, respectively. In addition, β-catenin expression is significantly decreased in more aggressive and metastatic melanoma. Multiple observational studies have shown smokers to have significantly lower rates of PD as well as melanoma implying that tobacco may contain one or more elements that protect against both conditions. In support, smoker's brains have significantly reduced levels of α-synuclein, a pathological intracellular protein found in PD brain and melanoma cells. Tobacco contains very high lithium levels compared to other plants. Lithium has a broad array of neuroprotective actions, including enhancing autophagy and reducing intracellular α-synuclein levels, and is effective in both neurotoxin and transgenic preclinical PD models. One of lithium's neuroprotective actions is enhancement of β-catenin-mediated activity leading to increased Nurr1 expression through its ability to inhibit glycogen synthase kinase-3 β (GSK-3β). Lithium also has anti-proliferative effects on melanoma cells and the clinical use of lithium is associated with a reduced incidence of melanoma as well as reduced melanoma-associated mortality. This is the first known report hypothesizing that inhaled lithium from smoking may account for the associated reduced rates of both PD and melanoma and that this protection may be mediated, in part, through lithium-induced GSK-3β inhibition and consequent enhanced β-catenin-mediated activity. This hypothesis could be directly tested in clinical trials assessing lithium therapy's ability to affect β-catenin-mediated activity and slow disease progression in patients with PD or melanoma.
SN - 1532-2777
UR - https://www.unboundmedicine.com/medline/citation/31443765/High_lithium_levels_in_tobacco_may_account_for_reduced_incidences_of_both_Parkinson's_disease_and_melanoma_in_smokers_through_enhanced_β_catenin_mediated_activity_
L2 - https://linkinghub.elsevier.com/retrieve/pii/S0306-9877(19)30463-3
DB - PRIME
DP - Unbound Medicine
ER -
