Oncogenic BRAFV600E induces microglial proliferation through extracellular signal-regulated kinase and neuronal death through c-Jun N-terminal kinase.

Activating V600E in v-Raf murine sarcoma viral oncogene homolog B (BRAF) is a common driver mutation in cancers of multiple tissue origins, including melanoma and glioma. BRAFV600E has also been implicated in neurodegeneration. The present study aims to characterize BRAFV600E during cell death and proliferation of three major cell types of the central nervous system: neurons, astrocytes, and microglia. Multiple primary cultures (primary cortical mixed culture) and cell lines of glial cells (BV2) and neurons (SH-SY5Y) were employed. BRAFV600E and BRAFWT expression was mediated by lentivirus or retrovirus. Blockage of downstream effectors (extracellular signal-regulated kinase 1/2 and JNK1/2) were achieved by siRNA. In astrocytes and microglia, BRAFV600E induces cell proliferation, and the proliferative effect in microglia is mediated by activated extracellular signal-regulated kinase, but not c-Jun N-terminal kinase. Conditioned medium from BRAFV600E-expressing microglia induced neuronal death. In neuronal cells, BRAFV600E directly induces neuronal death, through c-Jun N-terminal kinase but not extracellular signal-regulated kinase. We further show that BRAF-related genes are enriched in pathways in patients with Parkinson's disease. 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.

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

Patients with Parkinson's disease (PD) generally have reduced risk of developing many types of cancers, except melanoma-a malignant tumor of melanin-producing cells in the skin. For decades, a large number of epidemiological studies have reported that the occurrence of melanoma is higher than expected among subjects with PD, and the occurrence of PD is reciprocally higher than expected among patients with melanoma. More recent epidemiological studies further indicated a bidirectional association, not only in the patients themselves but also in their relatives. This association between PD and melanoma offers a unique opportunity to understand PD. Here, we summarize epidemiological, clinical, and biological evidence in regard to shared risk factors and possible underlying mechanisms for these two seemingly distinct conditions.