Degeneration of dopaminergic neurons in the substantia nigra causes the motor symptoms of Parkinson’s disease. The mechanisms underlying this age-dependent and region-selective neurodegeneration remain unclear. Here we identify Cav2.3 channels as regulators of nigral neuronal viability. Cav2.3 transcripts were more abundant than other voltage-gated Ca2+ channels in mouse nigral neurons and upregulated during aging. Plasmalemmal Cav2.3 protein was higher than in dopaminergic neurons of the ventral tegmental area, which do not degenerate in Parkinson’s disease. Cav2.3 knockout reduced activity-associated nigral somatic Ca2+ signals and Ca2+-dependent after-hyperpolarizations, and afforded full protection from degeneration in vivo in a neurotoxin Parkinson’s mouse model. Cav2.3 deficiency upregulated transcripts for NCS-1, a Ca2+-binding protein implicated in neuroprotection. Conversely, NCS-1 knockout exacerbated nigral neurodegeneration and downregulated Cav2.3. Moreover, NCS-1 levels were reduced in a human iPSC-model of familial Parkinson’s. Thus, Cav2.3 and NCS-1 may constitute potential therapeutic targets for combatting Ca2+-dependent neurodegeneration in Parkinson’s disease.

Glioblastoma (GB) is a highly aggressive, difficult to treat brain tumour. Successful treatment, consisting of maximal safe tumour de-bulking, followed by radiotherapy and treatment with the alkylating agent Temozolomide (TMZ), can extend patient survival to approximately 15 months. Combination treatments based on the inhibition of the PI3K pathway, which is the most frequently activated signalling cascade in GB, have so far only shown limited therapeutic success. Here, we use the clinically approved MEK inhibitor Trametinib to investigate its potential use in managing GB. Trametinib has a strong anti-proliferative effect on established GB cell lines, stem cell-like cells and their differentiated progeny and while it does not enhance anti-proliferative and cell death-inducing properties of the standard treatment, i.e. exposure to radiation or TMZ, neither does MEK inhibition block their effectiveness. However, upon MEK inhibition some cell populations appear to favour cellsubstrate interactions in a sprouting assay and become more invasive in the Chorioallantoic Membrane assay, which assesses cell penetration into an organic membrane. While this increased invasion can be modulated by additional inhibition of the PI3K signalling cascade, there is no apparent benefit of blocking MEK compared to targeting PI3K. Glioblastoma (GB), formerly Glioblastoma multiforme, is the most common primary brain tumour in adults and-due to its aggressive and highly infiltrative nature-among the most lethal malignancies per se 1. The current standard therapy involves maximum safe surgical resection followed by radio-and chemotherapy with the alkylating agent Temozolomide (TMZ) 2 which leads to a mean patient survival of only 15 months 3. Although GB only rarely metastasised outside the neuraxis, upon clinical presentation it will almost invariably have infiltrated the surrounding brain tissue, impeding full surgical resection and resulting in tumour recurrence 4. GB exhibits a rather low mutational burden 5 , with the most consistent alterations found in the PI3K signalling cascade, which is activated in ~88% of all GBs 6,7. Despite intensive efforts to translate modulation of this signalling pathway into a clinical setting, so far, only two mTOR (a downstream modulator of PI3K signalling) inhibitors, Everolimus and Temsirolimus, have been approved for clinical use 8. This might be, at least in part, due to the complexity of the PI3K pathway, while frequently reduced to a "survival pathway" in the context of cancer research, this network has several distinct and somehow competing functions 9,10. In our hands, inhibition of PI3K signalling in differentiated GB cells (DGBCs) only weakly reduces their proliferation and has little effect on their resistance to apoptosis; however, it strongly reduces their motility. In contrast the motility of the corresponding stem cell-like cells (SCs) was not affected, but the increased resistance of SCs compared to DGBCs with regard to apoptosis induction, seems to be mediated, at least in part, by PI...