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Research finds that disruption of mitochondria-associated membrane in neurons as a possible pathological basis for Amyotrophic lateral sclerosis

A schematic illustration for MAM disruption in ALS. IP3R3, a MAM specific Ca2+ channel (an orange arrow, left), was
mislocalized from the MAM in the ALS model mice (white arrow heads, right). Credit: Koji Yamanaka laboratory

Amyotrophic lateral sclerosis (ALS) is an adult onset, fetal neurodegenerative disease that selectively affects motor neurons. To date, more than 20 genes are identified as a causative of inherited Amyotrophic lateral sclerosis. A research team led by Prof. Koji Yamanaka (Nagoya University) found that collapse of the mitochondria-associated membrane is a common pathological hallmark to two distinct inherited forms of ALS: SOD1– and SIGMAR1– linked Amyotrophic lateral sclerosis. The research findings were reported in EMBO Molecular Medicine.

The researchers focused on the mitochondria-associated membrane (MAM), which is a contacting site of mitochondria and endoplasmic reticulum (ER). Recent studies have revealed that the mitochondria-associated membrane plays a key role in cellular homeostasis, such as lipid synthesis, protein degradation, and energy metabolism. Intriguingly, a recessive mutation in SIGMAR1 gene, which encodes sigma 1 receptor (Sig1R), a chaperone enriched in the mitochondria-associated membrane, is causative for a juvenile ALS. In this study, the researchers identified a novel Amyotrophic lateral sclerosis linked SIGMAR1 mutation, c.283dupC/p.L95fs in a juvenile-onset Amyotrophic lateral sclerosis case. Moreover, Amyotrophic lateral sclerosis linked Sig1R mutant proteins were unstable and non-functional, indicating a loss-of function mechanism in SIGMAR1-linked Amyotrophic lateral sclerosis.

A loss of Sig1R function induced mitochondria-associated membrane disruption in neurons. However, it was still unknown whether the mitochondria-associated membrane alternation was also involved in the other Amyotrophic lateral sclerosis cases. To address this question, the researchers cross-bred SIGMAR1 deficient mice with the other inherited Amyotrophic lateral sclerosis mice which overexpress a mutant form of SOD1 gene. SIGMAR1 deficiency accelerated disease onset of SOD1-Amyotrophic lateral sclerosis mice by more than 20 %. In those mice, inositol triphosphate receptor type-3 (IP3R3), a mitochondria-associated membrane enriched calcium ion (Ca2+) channel on ER, was disappeared from the mitochondria-associated membrane. The loss of proper localization of IP3R3 led to Ca2++ dysregulation to exacerbate the neurodegeneration. The researchers also found that IP3R3 was selectively enriched in motor neurons, suggesting that integrity of the mitochondria-associated membrane is crucial for the selective vulnerability in Amyotrophic lateral sclerosis.

These results provide us with new perspectives regarding future therapeutics, especially focused on preventing the mitochondria-associated membrane disruption for Amyotrophic lateral sclerosis patients. Together with the research from other groups, collapse of the mitochondria-associated membrane is widely observed in the other genetic causes of Amyotrophic lateral sclerosis, and therefore it may be applicable to sporadic Amyotrophic lateral sclerosis patients.

Citation: Seiji Watanabe, Hristelina Ilieva, Hiromi Tamada, Hanae Nomura, Okiru Komine, Fumito Endo, Shijie Jin, Pedro Mancias, View ORCID ProfileHiroshi Kiyama, Koji Yamanaka. “Mitochondria‐associated membrane collapse is a common pathomechanism in SIGMAR1‐ and SOD1‐linked ALS” EMBO Molecular Medicine  2016 vol: 34 (36) pp: 12093-1210
Research funding: Japan Ministry for Education, Culture and Sports, Science and Technology, Japan Agency for Medical Research and Development, Naito Foundation, Uehara Memorial Foundation, Japan ALS Association, Hori Science and Arts Foundation.
Press release by Nagoya University

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