Regulation of lysosomal function by ryanodine receptormediated Ca2+ release in health and disease

 Disruption of lysosomal function is an early event in the development of Alzheimer’s disease (AD). The origin of this lysosomal dysfunction is still extensively studied and may be directly related to intracellular accumulation of AD associated amyloid beta in the lysosomes impairing their function. Another early event in AD is the dysregulation of intracellular Ca2+ release which impacts among other processes memory formation. Excessive activity of the endoplasmic reticulum located ryanodine receptor (RyR) Ca2+ release channel has been extensively reported to contribute to this disrupted intracellular Ca2+ release. As a consequence blocking RyR activity was shown to be beneficial for slowing down disease progression in mouse models. During my PhD. and junior post-doctoral work we identified antiapoptotic Bcl-2 proteins as inhibitors of RyR-mediated Ca2+ release. We also showed that, chemical blockade of spontaneous RyR activity increases autophagic flux at the level of the lysosomes. This suggests that RyRs influence certain aspects of lysosomal function. In this project we will link together both findings and address how RyR-mediated Ca2+ release regulates lysosomal function. Next, we will apply these findings to AD models. By modulating RyR activity in these models, either using chemical inhibitors or Bcl-2 proteins, we will address whether RyR inhibition normalizes both excessive intracellular Ca2+ release and lysosomal dysfunction both associated with AD.