Mutations in P/Q type voltage gated calcium channel (VGCC) lead severe human neurological diseases such as episodic ataxia 2, familial hemiplegic migraine 1, absence epilepsy, progressive ataxia and spinocerebellar ataxia 6. The pathogenesis of these diseases remains unclear. Mice with spontaneous mutation in the Cacna1a gene encoding the pore-forming subunit of P/Q type VGCC also exhibit ataxia, epilepsy and neurodegeneration. Based on the previous work showing that the P/Q type VGCC in neurons regulates lysosomal fusion through its calcium channel activity on lysosomes, we utilized CACNA1A mutant mice to further investigate the mechanism by which P/Q-type VGCCs regulate lysosomal function and neuronal homeostasis. We found CACNA1A mutant neurons have reduced lysosomal calcium storage without changing the resting calcium concentration in cytoplasm and the acidification of lysosomes. Immunohistochemistry and transmission electron microscopy reveal axonal degeneration due to lysosome dysfunction in the CACNA1A mutant cerebella. The calcium modulating drug thapsigargin, by depleting the ER calcium store, which locally increases the calcium concentration can alleviate the defective lysosomal fusion in mutant neurons. We propose a model that in cerebellar neurons, P/Q-type VGCC maintains the integrity of the nervous system by regulating lysosomal calcium homeostasis to affect lysosomal fusion, which in turn regulates multiple important cellular processes such as autophagy and endocytosis. This study helps us to better understand the pathogenesis of P/Q-type VGCC related neurodegenerative diseases and provides a feasible direction for future pharmacological treatment.

P/Q 型电压门控钙通道 (VGCC) 突变导致严重的人类神经系统疾病，如发作性共济失调 2、家族性偏瘫偏头痛 1、失神性癫痫、进行性共济失调和脊髓小脑性共济失调 6。这些疾病的发病机制仍不清楚。Cacna1a自发突变的小鼠编码 P/Q 型 VGCC 的成孔亚基的基因也表现出共济失调、癫痫和神经退行性变。基于先前的工作表明神经元中的P/Q型VGCC通过其在溶酶体上的钙通道活性调节溶酶体融合，我们利用CACNA1A突变小鼠进一步研究了P/Q型VGCC调节溶酶体功能和神经元稳态的机制。 . 我们发现 CACNA1A 突变神经元减少了溶酶体钙的储存，而不会改变细胞质中的静息钙浓度和溶酶体的酸化。免疫组织化学和透射电子显微镜显示 CACNA1A 突变小脑中溶酶体功能障碍导致的轴突变性。钙调节药物毒胡萝卜素，通过消耗 ER 钙储存，局部增加钙浓度可以缓解突变神经元中有缺陷的溶酶体融合。我们提出了一个模型，即在小脑神经元中，P/Q 型 VGCC 通过调节溶酶体钙稳态以影响溶酶体融合来维持神经系统的完整性，进而调节多个重要的细胞过程，如自噬和内吞作用。本研究有助于我们更好地了解P/Q型VGCC相关神经退行性疾病的发病机制，为未来的药物治疗提供可行的方向。这反过来又调节多个重要的细胞过程，例如自噬和内吞作用。本研究有助于我们更好地了解P/Q型VGCC相关神经退行性疾病的发病机制，为未来的药物治疗提供可行的方向。这反过来又调节多个重要的细胞过程，例如自噬和内吞作用。本研究有助于我们更好地了解P/Q型VGCC相关神经退行性疾病的发病机制，为未来的药物治疗提供可行的方向。