Enhanced calcium release in the acute neuronopathic form of Gaucher disease

Gaucher disease is an inherited metabolic disorder caused by defective activity of the lysosomal enzyme, glucocerebrosidase, resulting in accumulation of the lipids, glucosylceramide (GlcCer), and glucosylsphingosine (GlcSph). Little is known about the mechanism leading from lipid accumulation to disease, particularly in the acute and subacute neuronopathic forms of Gaucher disease, types 2 and 3, respectively. Recent work from our laboratory has shown, in animal models, that GlcCer enhances agonist-induced calcium release from intracellular stores via the ryanodine receptor, which results in neuronal cell death. We now test whether calcium release is altered in human brain tissue obtained post-mortem from Gaucher disease patients. Agonist-induced calcium release via the ryanodine receptor was significantly enhanced (P < 0.05) in brain microsomes from the acute neuronopathic form of Gaucher disease (type 2) (43 ± 6% of the calcium in microsomes) compared to the subacute (type 3) (27 ± 3%) and the non-neuronopathic (type 1) (28 ± 6%) forms, and controls (18 ± 3%), and correlated with levels of GlcCer accumulation. These findings suggest that defective calcium homeostasis may be a mechanism responsible for neuropathophysiology in acute neuronopathic Gaucher disease, and may potentially offer new therapeutic approaches for disease management

Different Mechanisms of Cell Death in Radiosensitive and Radioresistant P53 Mutated Head and Neck Squamous Cell Carcinoma Cell Lines Exposed to Carbon Ions and X-Rays

Purpose We initiated studies on the mechanisms of cell death in head and neck squamous cell carcinoma cell lines (HNSCC) since recent clinical trials have shown that local treatment of HNSCC by carbon hadrontherapy is less efficient than it is in other radioresistant cancers. Methods and Materials Two p53-mutated HNSCC cell lines displaying opposite radiosensitivity were used. Different types of cell death were determined after exposure to carbon ions (33.6 and 184 keV/μm) or X-rays. Results Exposure to radiation with high linear energy transfer (LET) induced clonogenic cell death for SCC61 (radiosensitive) and SQ20B (radioresistant) cells, the latter systematically showing less sensitivity. Activation of an early p53-independent apoptotic process occurred in SCC61 cells after both types of irradiation, which increased with time, dose and LET. In contrast, SQ20B cells underwent G2/M arrest associated with Chk1 activation and Cdc2 phosphorylation. This inhibition was transient after X-rays, compared with a more prolonged and LET-dependent accumulation after carbon irradiation. After release, a LET-dependent increase of polyploid and multinucleated cells, both typical signs of mitotic catastrophe, was identified. However, a subpopulation of SQ20B cells was able to escape mitotic catastrophe and continue to proliferate. Conclusions High LET irradiation induced distinct types of cell death in HNSCC cell lines and showed an increased effectiveness compared with X-rays. However, the reproliferation of SQ20B may explain the potential locoregional recurrence observed among some HNSCC patients treated by hadrontherapy. An adjuvant treatment forcing the tumor cells to enter apoptosis may therefore be necessary to improve the outcome of radiotherapy