Unusual expansion of polyQ repeats in certain proteins causes a group of progressive neurodegenerative diseases and Huntington's disease (HD) is one of them. Atypical expansion of trinucleotide repeats, CAG (>35), in the exon-I of the gene coding for the huntingtin protein results in pathological manifestation due to the mutant protein (mHtt), which damages the neurons by multiple mechanisms (Bates et al., 2015). Misfolding of the mutant protein results in the formation of insoluble aggregates in the brain and other affected tissues, and hampers cellular activities (Steffan et al., 2001). MHtt disrupts calcium signaling in various ways such as altering mitochondrial homeostasis, affecting ATP synthesis and production of reactive oxygen species (ROS) (Kann and Kovács, 2007), and hampering cell survival pathways (Monzio Compagnoni et al., 2020). Mitochondrial dysfunction is associated with neurodegenerative diseases (Monzio Compagnoni et al., 2020), as well as increased susceptibility to oxidative mitochondrial injury in the central nervous system neurons due to a deficiency of superoxide dismutase II (SOD2) (Lebovitz et al., 1996). Loss of neuronal function by impaired axonal activity, mitochondrial dysfunction, and oxidative stress (Ross and Tabrizi, 2011), recruits cell death molecules such as caspases to eliminate the damaged neurons from the system. Multiple factors such as the activation of caspases and reduction of inhibitors of apoptosis (IAPs) proteins contribute to neuronal death (Schwerk and Schulze-Osthoff, 2003). Bcl-2, an IAP, interacts with SERCA to modulate the cytosolic and ER [Ca2+] level hence regulating cell death (Dremina et al., 2004). Conversely enhancing Yes-associated protein (YAP/TAZ), or its Drosophila homolog Yorkie (Yki) (Mo et al., 2014) leads to cell proliferation and rescue in polyQ mediated neurodegeneration in Huntington's disease (Dubey and Tapadia, 2018), is also affected by [Ca2+] levels.

Considering the importance of [Ca2+] ions in the maintenance of neurons and neurotransmission in all organisms (Bezprozvanny, 2010), their levels in different compartments of the cells have to be precisely controlled. [Ca2+] is released from its primary reservoir, endoplasmic reticulum (ER), into the cytoplasm through inositol-1,4,5-trisphosphate receptors (IP3Rs) (Berridge, 2009; Bezprozvanny, 2005; Mikoshiba, 2007), ryanodine receptors (RyRs) (Rossi and Sorrentino, 2002) and passive leakage (Van Coppenolle et al., 2004; Tu et al., 2006; Supnet and Bezprozvanny, 2011). Depletion of [Ca2+] in the ER is sensed by stromal interacting molecules (STIMs) on the ER membrane, which oligomerize and move near the plasma membrane and interact with [Ca2+] conducting channels that replenish [Ca2+] from extracellular space through channels which include voltage-gated [Ca2+] channels (VGCC), N-methyl-D aspartate neuron receptors (NMDAR), [Ca2+]-conducting α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors, canonical transient receptor potential channels (TRPC), and release-activated channels (CRAC) in the plasma membrane. [Ca2+] is imported back into the ER via SERCA pump which plays a very crucial role in maintaining [Ca2+] homeostasis and preventing neuronal cell death (Betzer and Jensen, 2018; Betzer et al., 2018).

The present work investigates the potential role of SERCA in the expanded polyQ-mediated neurodegeneration in Drosophila. We observe that though SERCA expression is reduced in polyQ-expressing cells, ER [Ca2+] levels are significantly higher and cytosolic [Ca2+] are considerably low than control. Bringing SERCA mutant with polyQ expressing cells results in the restoration of the structural and functional defects of the neurons. Reduced autophagic response and reduced ROS production promote cell survival pathways. These results imply that neurodegeneration due to expanded polyQ repeats is sensitive to SERCA inhibition. We show that interaction between SERCA and DIAP1 could be an important modifier of SERCA activity, which rescues polyQ-mediated pathogenesis by interfering with the apoptotic and autophagic pathways. The present results support SERCA to be a critical mediator of the polyQ pathogenesis and interaction between polyQ aggregates, SERCA and DIAP1 could be playing an important role in maintaining cellular calcium levels.