REVIEW ARTICLE published: 30 May 2014 doi: 10.3389/fncel.2014.00147 The ER mitochondria calcium cycle and ER stress response as therapeutic targets in amyotrophic lateral sclerosis VedranaTadic*,Tino Prell, Janin Lautenschlaeger and Julian Grosskreutz Hans Berger Department of Neurology, Jena University Hospital, Jena, Germany Edited by: Manoj Kumar Jaiswal, Center for Neuroscience and Regenerative Medicine, USA Reviewed by: Tibor Kristian, University of Maryland School of Medicine, USA Alexej Verkhratsky, University of Manchester, UK Pavle R. Andjus, University of Belgrade, Serbia Anthony Robert White, The University of Melbourne, Australia *Correspondence: VedranaTadic, Hans Berger Department of Neurology, Jena University Hospital, Erlanger Allee 101, 07747 Jena, Germany e-mail: vedrana.tadic@ med.uni-jena.de Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by progressive loss of upper and lower motor neurons. Although the etiology remains unclear, disturbances in calcium homoeostasis and protein folding are essential features of neurodegeneration in this disorder. Here, we review recent research findings on the interaction between endoplasmic reticulum (ER) and mitochondria, and its effect on calcium signaling and oxidative stress.We further provide insights into studies, providing evidence that structures of the ER mitochondria calcium cycle serve as a promising targets for therapeutic approaches for treatment of ALS. Keywords: amyotrophic lateral sclerosis, ER stress, protein misfolding, calcium dysregulation, SOD1, TDP-43, mitochondria, oxidative stress INTRODUCTION Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder characterized by progressive degeneration of the upper (spasticity, dysphagia, dysarthria) and lower motor neurons (atro- phy, fasciculations). Approximately 90% of ALS patients have sporadic ALS (sALS) which is the most prevalent form and about 10% have the inherited or familial form of ALS (fALS). The lat- ter form is believed to be due to several genes including SOD1, Abbreviations: ALS, amyotrophic lateral sclerosis; AMPA, α-amino-5-methyl- 3-hydroxisoxazolone-4-propionate; ANT, adenine nucleotide translocator; AP-1, activator protein 1; ARE, antioxidant response element; ATF6, basic leucine-zipper transcription factor 6; Bax/Bak, Bcl-2-associated X protein; Bcl-2, B-cell lymphoma 2 protein; BIK, Bcl-2 interacting killer protein; C9ORF72, chromosome 9 open reading frame 72; CHOP, transcription factor C/EBP homologous protein; eIF2α, eukaryotic initiation factor-2; ER, endoplasmic reticulum; ERMCC, endoplasmic reticulum mitochondria calcium cycle; fALS, familial amyotrophic lateral sclerosis; FUS/TSL, fused in sarcoma/translated in liposarcoma; HIF-1α, hypoxia-induced factor; Hsf1, heat shock transcription factor 1; InsP3, inositol 1,4,5-trisphosphate; IP 3 R, inositol 1,4,5-triphosphate receptor-gated channel; IRE1, inositol-requiring enzyme 1; mNCE, mitochondrial sodium calcium exchanger; mPTP, mitochondrial permeability transition pore; mUP, mitochondrial uniporter; NF-κB, nuclear factor kappa-light-chain-enhancer of activated B cells; NO, nitric oxide; Nrf2, erythroid 2-related-factor 2; OPTN, optineurin; PDI, protein disulfide isomerase; PERK, the double-stranded RNA-activated protein kinase (PKR)-like ER kinase; PLCδ1, phospolipase C delta 1; ROS, reactive oxygen species; RyR, ryanodine receptors; sALS, sporadic amyotrophic lateral sclerosis; SERCA, sarco/endoplasmic reticulum Ca 2 + ATPase; SOD1, Cu/Zn superoxide dismutase type 1; SR, sarcoplasmic reticu- lum; TARDBP, TAR DNA binding protein; TCTP, translationally controlled tumor protein; TDP-43, transactive response DNA binding protein 43 kDa; UBQLN2, ubiquilin-2; UCH-L1, ubiquitin carboxy-terminal hydrolase L1; UPR,unfolded pro- tein response; VAPB, vesicle-associated membrane protein (VAMP)-associated pro- tein B; VCP, valosin-containing protein; VDAC, voltage-dependent anion channel. TARDBP, FUS, OPTN, and VCP. In addition, a hexanucleotide (GGGGCC) repeat expansion in the first intron of the C9ORF72 gene (DeJesus-Hernandez et al., 2011; Renton et al., 2011) has lately been demonstrated as being associated with ALS. How- ever, the etiology of the disease is still unclear, although recent studies indicate that calcium (Ca 2 + ) disturbances, ER stress, and mitochondrial dysfunction are involved in the pathogenesis of ALS (Grosskreutz et al., 2010; Lautenschlaeger et al., 2012). Other mechanisms possibly involved in ALS-related pathophysiology comprise: oxidative stress, protein aggregation, dysregulated endo- somal trafficking, impaired axonal transport, neuroinflammation, and dysregulated transcription and RNA processing (Ferraiuolo et al., 2011). Several properties of motor neurons make them more vulnerable than other neuronal groups. Motor neurons express high levels of Ca 2 + –permeable α-amino-5-methyl-3- hydroxisoxazolone-4-propionate (AMPA) receptors that lack the GluR2 subunit which makes them more vulnerable to excitotoxic- ity and dysregulation of intracellular Ca 2 + homeostasis (Williams et al., 1997). Also, low levels of Ca 2 + -buffering proteins con- tributes greatly to this vulnerability (Ince et al., 1993). Because of high metabolic demands, motor neurons are largely depen- dent on optimal mitochondrial function, a robust cytoskeleton and an axonal transport mechanism. Despite all the above facts, there remain numerous unanswered questions in ALS related to selectivity and specificity of the cellular targets of motor neuron degeneration and cell-specific aspects of mitochondrial Ca 2 + signaling. This review focuses on crosstalk between ER, mitochondria, oxidative stress and calcium. Frontiers in Cellular Neuroscience www.frontiersin.org May 2014 | Volume 8 | Article 147 | 1