News Release
Title
Elucidating the mechanism of disrupted proteostatic stress response mediatedby the mitochondria-associated membranes in amyotrophic lateral sclerosis(ALS)Key Points⚫

Levels of active TANK-binding kinase 1 (TBK1), an ALS-causing geneproduct, were reduced in the affected tissues of ALS patients and mousemodels.

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The reduced TBK1 activity in ALS was associated with disruption of theendoplasmic reticulum-mitochondrial contacts.

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MAM-dependent activation of TBK1 was crucial for neuronal stressresponses, especially for protein homeostasis.

Figure. Schematic outline of this study (left) and activation of TBK1 at theMAM (B)SummaryA research group led by Dr. Seiji Watanabe (first author), Prof. Koji Yamanaka(Department
Environmentalof

Neuroscience

Medicine(RIEM),&Pathobiology,Nagoya

ResearchUniversity),Prof.

InstituteofTomooOgi(Department of Genetics, RIEM, Nagoya University), and Prof. Masahisa
Katsuno (Department of Neurology, Graduate School of Medicine, Nagoya

University), and their colleagues have identified that disruption of themitochondria-associated membranes (MAM) in amyotrophic lateral sclerosis(ALS) causes a reduction in the activity of TANK-binding kinase 1 (TBK1),
leading to an abnormal stress response in motor neurons.
ALS is an intractable neurodegenerative disease that selectively affects themotor neurons. So far, the research group has shown that disruption of the MAM,
a region where the endoplasmic reticulum and mitochondria contact each other,is essential for the development of ALS. However, the mechanism by which MAM
disruption causes motor neuron degeneration was unclear.
The research group focused on TBK1, a key molecule in innate immunity andthe product of the ALS-causative gene, and found that TBK1 activation wasmarkedly reduced in brain and spinal cord tissues from ALS patients and micein which MAM had been genetically disrupted. These results suggest that MAM
disruption in ALS leads to a decrease in TBK1 activity. Moreover, motor
dysfunction was observed in mice with disrupted MAM when treated witharsenite, which was associated with reduced TBK1 activity.
This study suggests that MAM contributes to the stress response of motor
neurons via activation of TBK1 and that the decrease in TBK1 activity
associated with MAM disruption leads to motor neuron degeneration in ALS. The
results of this study are expected to lead to the development of new
therapeutic strategies for ALS in the future.
Publication“Mitochondria-associatedmembranecollapse

impairs

TBK1-mediatedproteostatic stress response in ALS.”

Proceedings of the National Academy of Sciences of the United States ofAmerica (November 15, 2023)
Seiji Watanabea, Yuri Murataa, Yasuyoshi Okab, Kotaro Oiwaa,c, Mai Horiuchia,
Yohei Iguchic, Okiru Kominea, Akira Sobuea,d, Masahisa Katsunoc,e, Tomoo Ogib,e,*Koji Yamanakaa,e,f
a Department of Neuroscience and Pathobiology, Research Institute ofEnvironmental Medicine, Nagoya University, Nagoya, Aichi, Japanb Department of Genetics, Research Institute of Environmental Medicine,
Nagoya University, Aichi, Japanc Department of Neurology, Nagoya University Graduate School of Medicine,
Nagoya, Aichi, Japand Medical Interactive Research and Academia Industry Collaboration Center,Research Institute of Environmental Medicine, Nagoya University, Aichi, Japane Institute for Glyco-core Research (iGCORE), Nagoya University, Aichi, Japanf Center for One Medicine Innovative Translational Research (COMIT), Nagoya
University, Nagoya, Aichi, Japan
DOI: 10.1073/pnas.2315347120
Japanese ver.
https://www.med.nagoya-u.ac.jp/medical_J/research/pdf/Pro_231116.pdf