Mitochondria‐associated membrane collapse is a common pathomechanism in SIGMAR1‐ and SOD1‐linked ALS. Issue 12 (7th November 2016)

• Record Type: Journal Article
• Authors: Watanabe, Seiji; Ilieva, Hristelina; Tamada, Hiromi; Nomura, Hanae; Komine, Okiru; Endo, Fumito; Jin, Shijie; Mancias, Pedro; Kiyama, Hiroshi; Yamanaka, Koji
• Is Part Of: EMBO molecular medicine. Volume 8:Issue 12(2016)
• Page Start: 1421
• Page End: 1437
• Publication Date: 2016-11-07
• Subjects: amyotrophic lateral sclerosis -- inositol 1, 4, 5‐triphosphate receptor type 3 -- mitochondria‐associated membrane -- sigma 1 receptor; Molecular biology -- Periodicals; Medical genetics -- Periodicals; Pathology, Molecular -- Periodicals; 616.04205
• DOI: 10.15252/emmm.201606403
• Languages: English
• ISSNs: 1757-4676

Abstract

Abstract: A homozygous mutation in the gene for sigma 1 receptor (Sig1R) is a cause of inherited juvenile amyotrophic lateral sclerosis (ALS16). Sig1R localizes to the mitochondria‐associated membrane (MAM), which is an interface of mitochondria and endoplasmic reticulum. However, the role of the MAM in ALS is not fully elucidated. Here, we identified a homozygous p.L95fs mutation of Sig1R as a novel cause of ALS16. ALS‐linked Sig1R variants were unstable and incapable of binding to inositol 1, 4, 5‐triphosphate receptor type 3 (IP3 R3). The onset of mutant Cu/Zn superoxide dismutase (SOD1)‐mediated ALS disease in mice was accelerated when Sig1R was deficient. Moreover, either deficiency of Sig1R or accumulation of mutant SOD1 induced MAM disruption, resulting in mislocalization of IP3 R3 from the MAM, calpain activation, and mitochondrial dysfunction. Our findings indicate that a loss of Sig1R function is causative for ALS16, and collapse of the MAM is a common pathomechanism in both Sig1R‐ and SOD1‐linked ALS. Furthermore, our discovery of the selective enrichment of IP3 R3 in motor neurons suggests that integrity of the MAM is crucial for the selective vulnerability in ALS. Synopsis: Mitochondria‐associated membranes (MAM) are contact sites between endoplasmic reticulum and mitochondria, and play a key role in cellular homeostasis. Here, disruption of the MAM is shown to be tightly involved in the pathology of amyotrophic lateral sclerosis (ALS). A novel ALS‐linked SIGMAR1 mutation, L95fs, is identified. ALS‐linked sigma 1 receptor (Sig1R) mutants are unstable and non‐functional, indicating loss‐of‐function mechanism in SIGMAR1 ‐linked ALS. Mutant SOD1 proteins are accumulated in the MAM, and a loss of Sig1R exacerbated the disease in mutant SOD1 transgenic mice. Collapse of the MAM is a common pathological hallmark both in SOD1 ‐ and SIGMAR1 ‐linked ALS mouse models. The selective enrichment of inositol triphosphate receptor type 3 (IP3 R3) in the MAM of motor neurons suggests that integrity of the MAM is crucial for the selective vulnerability in ALS. Abstract : Mitochondria‐associated membranes (MAM) are contact sites between endoplasmic reticulum and mitochondria and play a key role in cellular homeostasis. Here, disruption of the MAM is shown to be tightly involved in the pathology of amyotrophic lateral sclerosis (ALS).