ER Stress and Unfolded Protein Response in Amyotrophic Lateral Sclerosis Kohsuke Kanekura & Hiroaki Suzuki & Sadakazu Aiso & Masaaki Matsuoka Received: 1 December 2008 / Accepted: 15 January 2009 / Published online: 30 January 2009 # Humana Press Inc. 2009 Abstract Several theories on the pathomechanism of amyotrophic lateral sclerosis (ALS) have been proposed: misfolded protein aggregates, mitochondrial dysfunction, increased glutamate toxicity, increased oxidative stress, disturbance of intracellular trafficking, and so on. In parallel, a number of drugs that have been developed to alleviate the putative key pathomechanism of ALS have been under clinical trials. Unfortunately, however, almost all studies have finished unsuccessfully. This fact indicates that the key ALS pathomechanism still remains a tough enigma. Recent studies with autopsied ALS patients and studies using mutant SOD1 (mSOD1) transgenic mice have suggested that endoplasmic reticulum (ER) stress-related toxicity may be a relevant ALS pathomechanism. Levels of ER stress-related proteins were upregulated in motor neurons in the spinal cords of ALS patients. It was also shown that mSOD1, translocated to the ER, caused ER stress in neurons in the spinal cord of mSOD1 transgenic mice. We recently reported that the newly identified ALS- causative gene, vesicle-associated membrane protein-asso- ciated protein B (VAPB), plays a pivotal role in unfolded protein response (UPR), a physiological reaction against ER stress. The ALS-linked P56S mutation in VAPB nullifies the function of VAPB, resulting in motoneuronal vulnerability to ER stress. In this review, we summarize recent advances in research on the ALS pathomechanism especially addressing the putative involvement of ER stress and UPR dysfunction. Keywords Amyotrophic lateral sclerosis . ER stress . Unfolded protein response Introduction In 1869, a French neurologist Jean-Martin Charcot and his colleague Alexis Joffroy reported a strange phenomenon observed in two patients who died from progressive weakness and degeneration of both upper and lower motor neurons with gliosis. Despite over 135 years of vigorous investigations after the discovery of the disease, amyotro- phic lateral sclerosis (ALS), also known as Lou Gehrig disease, still remains a fatal merciless disorder that affects two to eight per 100,000 persons in the world [1]. ALS is characterized by progressive neurodegeneration specifically affecting both upper and motor neurons. Typical cases occur sporadically (∼90%) in their middle ages and become fatal within 2–5 years from the disease onset mostly because of respiratory failure while cognitive function of patients remains completely intact even in the terminal phase of the disease. Several ALS-specific pathological hallmarks have been identified [2–5]: the degeneration of motoneurons in the spinal anterior horn; the Bunina body, also known as Lewy body-like hyaline inclusion body, seen in the survived motoneurons; sphe- roids consisting of accumulated neurofilaments in the Mol Neurobiol (2009) 39:81–89 DOI 10.1007/s12035-009-8054-3 K. Kanekura : H. Suzuki : M. Matsuoka (*) Department of Cell Biology and Neuroscience, School of Medicine, Keio University, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan e-mail: sakimatu@sc.itc.keio.ac.jp K. Kanekura : H. Suzuki : S. Aiso Department of Anatomy, School of Medicine, Keio University, Tokyo, Japan H. Suzuki Japan Society for the Promotion of Science Research Fellow, Tokyo, Japan