Fig. 10

A summary of how loss-of- function variants can lead to autophagy. Calcium ions can enter into neuronal cell via Cav1.2, Cav1.4, Cavα2δ, Cav2.1, Cav2.2, Cav2.3, Cav3.1, Cav3.2 and Cav3.3. In normal physiology, some of the calcium ions go to the nucleus to initiate gene transcription, translation and protein synthesis essential for learning and memory, some go to mitochondria for ATP synthesis (essential for learning and memory) and some to the endoplasmic reticulum for storage. Calcium stored in the endoplasmic reticulum (ER) is used when there is minimal/no influx of calcium ions inside the cells. Autophagy occurs when there is metabolic stress such as low ATP and nutrient starvation. Low levels of calcium ions inside the neuronal cell being due to loss-of- function of calcium channels or due to depletion in ER can activate autophagy pathway. Low calcium entrance in the mitochondria will lead to low production of ATP which will activate the AMP-activated protein kinase (AMPK, a sensor of energy levels) and mTOR complex 1 (mTORC1) which in turn induce autophagy. Likewise, low calcium levels from the ER can activate calmodulin-dependent protein kinase kinase β (CaMKKβ) and then AMPK leading to autophagy. Dotted arrows signify low levels. Few red solid circles stand for low calcium ions levels