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

Study demonstrates role of gut bacteria in neurodegenerative diseases

Alzheimer’s disease (AD), Parkinson’s disease (PD) and Amyotrophic Lateral Sclerosis (ALS) are all characterized by clumped, misfolded proteins and inflammation in the brain. In more than 90 percent of cases, physicians and scientists do not know what causes these processes to occur.

Robert P. Friedland, M.D., the Mason C. and Mary D. Rudd Endowed Chair and Professor of Neurology at the University of Louisville School of Medicine, and a team of researchers have discovered that these processes may be triggered by proteins made by our gut bacteria (the microbiota). Their research has revealed that exposure to bacterial proteins called amyloid that have structural similarity to brain proteins leads to an increase in clumping of the protein alpha-synuclein in the brain. Aggregates, or clumps, of misfolded alpha-synuclein and related amyloid proteins are seen in the brains of patients with the neurodegenerative diseases AD, PD and ALS. This research is published online Oct. 6 in Scientific Reports, a journal of the Nature Publishing Group.

Alpha-synuclein (AS) is a protein normally produced by neurons in the brain. In both PD and AD, alpha-synuclein is aggregated in a clumped form called amyloid, causing damage to neurons. Friedland has hypothesized that similarly clumped proteins produced by bacteria in the gut cause brain proteins to misfold via a mechanism called cross-seeding, leading to the deposition of aggregated brain proteins. He also proposed that amyloid proteins produced by the microbiota cause priming of immune cells in the gut, resulting in enhanced inflammation in the brain.

The research, which was supported by The Michael J. Fox Foundation, involved the administration of bacterial strains of E. coli that produce the bacterial amyloid protein curli to rats. Control animals were given identical bacteria that lacked the ability to make the bacterial amyloid protein. The rats fed the curli-producing organisms showed increased levels of AS in the intestines and the brain and increased cerebral AS aggregation, compared with rats who were exposed to E. coli that did not produce the bacterial amyloid protein. The curli-exposed rats also showed enhanced cerebral inflammation.

Similar findings were noted in a related experiment in which nematodes (Caenorhabditis elegans) that were fed curli-producing E. coli also showed increased levels of AS aggregates, compared with nematodes not exposed to the bacterial amyloid. A research group led by neuroscientist Shu G. Chen, Ph.D., of Case Western Reserve University, performed this collaborative study.

This new understanding of the potential role of gut bacteria in neurodegeneration could bring researchers closer to uncovering the factors responsible for initiating these diseases and ultimately developing preventive and therapeutic measures.

“These new studies in two different animals show that proteins made by bacteria harbored in the gut may be an initiating factor in the disease process of Alzheimer’s disease, Parkinson’s disease and ALS,” Friedland said. “This is important because most cases of these diseases are not caused by genes, and the gut is our most important environmental exposure. In addition, we have many potential therapeutic options to influence the bacterial populations in the nose, mouth and gut.”

This work supports recent studies indicating that the microbiota may have a role in disease processes in age-related brain degenerations. It is part of Friedland’s ongoing research on the relationship between the microbiota and age-related brain disorders, which involves collaborations with researchers in Ireland and Japan.

“We are pursuing studies in humans and animals to further evaluate the mechanisms of the effects we have observed and are exploring the potential for the development of preventive and therapeutic strategies,” Friedland said.

Publication: Exposure to the Functional Bacterial Amyloid Protein Curli Enhances Alpha-Synuclein Aggregation in Aged Fischer 344 Rats and Caenorhabditis elegans.
Study demonstrates role of gut bacteria in neurodegenerative diseases