Chronic Inflammation Links Cancer and Parkinson's Disease

Abstract

An increasing number of genetic studies suggest that the pathogenesis of Parkinson's disease (PD) and cancer share common genes, pathways, and mechanisms. Despite a disruption in a wide range of similar biological processes, the end result is very different: uncontrolled proliferation and early neurodegeneration. Thus, the links between the molecular mechanisms that cause PD and cancer remain to be elucidated. We propose that chronic inflammation in neurons and tumors contributes to a microenvironment that favors the accumulation of DNA mutations and facilitates disease formation. This article appraises the key role of microglia, establishes the genetic role of COX2 and CARD15 in PD and cancer, and discusses prevention and treatment with this new perspective in mind. We examine the evidence that chronic inflammation is an important link between cancer and PD.

Keywords: CARD15; COX2; PD; cancer; chronic inflammation; microglia.

FIGURE 1

Genes and biological processes shared in Parkinson’s disease (PD) and cancer. Overlapping biological processes of PD and cancer mainly include the following: (a) misfolding and degradation of proteins, (b) mitochondrial damage and oxidative stress response, (c) chronic inflammation, (d) cell cycle control and DNA repair, and (e) PI3K/AKT/mTOR pathway regulation. The α-synuclein polymer attributed to SNCA multiplication is the main component of Lewy bodies (LBs). SNCA mutations alter the normal function of α-synuclein, which induces the PI3K/AKT/mTOR pathway and promotes cell proliferation. Under the cascade of phosphorylating AKT, mTOR is activated by PINK1 and LRRK2. PARK2 and UCH-L1 mutations disrupt the degradation function of the ubiquitin proteasome system (UPS), leading to the misfolding and aggregation of α-synuclein, cyclin E, and p53. PINK1 and DJ-1 mutations result in the overproduction of free radicals and oxidative stress in the mitochondria, which causes neuron defects and stimulates cell proliferation. COX2 and CARD15 mutations activate the NF-κB pathway and induce chronic inflammation, leading to a wide range of genetic mutations and abnormal cellular signaling. The different cellular backgrounds of cancer cells and neurons (mitotic vs. post-mitotic cells) bring completely distinct reactions to external stimuli and internal changes: some undergo cell proliferation, and others neuron death. The final result is two serious diseases: cancer and PD.