神経変性疾患における神経喪失を阻止する新しい戦略の可能性を示す(New strategy shows potential to block nerve loss in neurodegenerative diseases)


軸索死を引き起こす重要な分子の働きを解明、新たな治療法につながる可能性 Research into how key molecule triggers axon death may lead to new therapies

2022-10-26 ワシントン大学セントルイス

Researchers at Washington University School of Medicine in St. Louis are working toward a treatment for neurodegenerative diseases that targets SARM1, a key molecule in the death of axons, the wiring of the nervous system. Shown, the axons (green) are thinner in a rodent model of an inherited axonal peripheral neuropathy (left). When SARM1 is missing from rodents with the disorder, the axons are thicker (right) and indistinguishable from normal, healthy axons. Finding ways to block SARM1 could lead to new therapies for a broad range of neurodegenerative diseases.



マクロファージ枯渇による先天性SARM1依存性ニューロパチーの阻止 Macrophage depletion blocks congenital SARM1-dependent neuropathy

Caitlin B Dingwall, Amy Strickland, Sabrina W Yum, Aldrin Kay-Yuen Yim , Jian Zhu , Peter L Wang, Yurie Yamada, Robert E Schmidt, Yo Sasaki, A Joseph Bloom, Aaron DiAntonio, Jeffrey Milbrandt
Journal of Clinical Investigation  Published:2022 Oct 26
DOI: 10.1172/JCI159800


Axon loss contributes to many common neurodegenerative disorders. In healthy axons, the axon survival factor NMNAT2 inhibits SARM1, the central executioner of programmed axon degeneration. We identified two rare NMNAT2 missense variants in two brothers afflicted with a progressive neuropathy syndrome. The polymorphisms resulted in amino acid substitutions, V98M and R232Q, which reduced NMNAT2 NAD+-synthetase activity. We generated a mouse model of the human syndrome and found that Nmnat2V98M/Nmnat2R232Q compound-heterozygous CRISPR mice survived to adulthood but developed progressive motor dysfunction, peripheral axon loss, and macrophage infiltration. These disease phenotypes were all SARM1-dependent. Remarkably, macrophage depletion therapy blocked and reversed neuropathic phenotypes in Nmnat2V98M/R232Q mice, identifying a SARM1-dependent neuroimmune mechanism as a key driver of disease pathogenesis. These findings demonstrate that SARM1 induces an inflammatory neuropathy and highlight the potential of immune therapy to treat this rare syndrome and other neurodegenerative conditions associated with NMNAT2 loss and SARM1 activation.

シャルコー・マリー・トゥース病2A型ラットモデルにおけるSARM1/ミトコンドリア・フィードバック・ループによる神経病態の解明 A SARM1/mitochondrial feedback loop drives neuropathogenesis in a Charcot-Marie-Tooth disease type 2A rat model

Yurie Yamada, Amy Strickland, Yo Sasaki, A Joseph Bloom, Aaron DiAntonio, Jeffrey Milbrandt
Journal of Clinical Investigation  Published:2022 Oct 26
DOI: 10.1172/JCI161566


Charcot-Marie-Tooth disease (CMT) type 2A is an axonal neuropathy caused by mutations in the mitofusin 2 (MFN2) gene. MFN2 mutations result in profound mitochondrial abnormalities, but the mechanism underlying axonal pathology is unknown. SARM1, the central executioner of axon degeneration, can induce neuropathy and is activated by dysfunctional mitochondria. We tested the role of SARM1 in a rat model carrying a dominant CMT2A mutation (Mfn2H361Y) that exhibits progressive dying-back axonal degeneration, NMJ abnormalities, muscle atrophy, and mitochondrial abnormalities, all hallmarks of the human disease. We generated Sarm1 knockout and Mfn2H361Y, Sarm1 double mutant rats and find that deletion of Sarm1 rescues axonal, synaptic, muscle, and functional phenotypes, demonstrating that SARM1 is responsible for much of the neuropathology in this model. Despite the presence of mutant MFN2 protein in these double mutant rats, loss of SARM1 also dramatically suppressed many mitochondrial defects, including the number, size, and cristae density defects of synaptic mitochondria. This surprising finding indicates that dysfunctional mitochondria activate SARM1, and activated SARM1 feeds back on mitochondria to exacerbate mitochondrial pathology. As such, this work identifies SARM1 inhibition as an exciting therapeutic candidate for the treatment of CMT2A and other neurodegenerative diseases with prominent mitochondrial pathology.