A novel role of Drosophila P/Q type voltage gated calcium channel subunits in autophagy. Upasana Gala¹, Chao Tong^2,3, Manish Jaiswal², Hector Sandoval², Shinya Yamamoto¹, Vafa Bayat¹, Bo Xiong¹, Ke Zhang⁴, Wu-Lin Charng¹, Lita Duraine⁵, Kartik Venkatachalam⁶, Hugo Bellen^1,2,5. 1) Program in Developmental Biology, BCM; 2) Department of Human and Molecular Genetics, BCM; 3) Department of Molecular Biology, Zhejiang University; 4) Structural & Computational Biology & Molecular Biophysics Program, BCM; 5) Howard Hughes Medical Institute; 6) Department of Integrative Pharmacology, UTHSC.

   Autophagy, characterized by the formation of a double membrane structure called autophagosome (AP) that sequesters intracellular cargo and delivers it to the lysosomes for proteolytic degradation, has been proposed to be especially important in long-lived post-mitotic neurons and defects in autophagy have been implicated in several neurodegenerative diseases (ND). We generated a collection of X chromosome mutants to identify essential genes in Drosophila involved in neurodegeneration. To find novel genes involved in autophagy that affect neuronal function, we re-screened this collection for defects in autophagy and identified ten alleles of cacophony (cac), the pore-forming 1 subunit of voltage gated calcium channel (VGCC). Transmission electron microscopy of eye-specific neurons in cac flies shows an accumulation of late stage autophagic vacuoles (AV), suggesting defects in AP maturation. Cac, its accessory subunits and the SNARE complex are involved in neurotransmitter release through synaptic vesicle fusion in a Ca2+-dependent manner. Surprised that Cac affected autophagy, we tested flies mutant for the VGCC 2 subunit, straightjacket and vamp7, a lysosomal SNARE protein and found that these phenocopy the cac mutants. Although Ca2+ and certain SNAREs have been shown to be required for autophagy, a VGCC has not previously been implicated in the autophagy pathway. We propose that Cac plays a role in autophagy by regulating the fusion of AVs with lysosomes. Mutations in VGCC subunits cause severe NDs such as spinocerebellar ataxia 6 and episodic ataxia type 2 but the molecular mechanisms are still undefined. We also propose that defects in Cac-mediated autophagy may be responsible for the aforementioned NDs.