SARM1 is responsible for calpain-dependent dendrite degeneration in mouse hippocampal neurons

被引:3
|
作者
Miyamoto, Takashi [1 ]
Kim, Chaeyoung [1 ]
Chow, Johann [1 ]
Dugas, Jason C. [1 ]
Degroot, Jack [1 ,2 ]
Bagdasarian, Alex L. [1 ]
Thottumkara, Arun P. [1 ,3 ]
Larhammar, Martin [1 ,4 ]
Calvert, Meredith E. K. [1 ]
Fox, Brian M. [1 ]
Lewcock, Joseph W. [1 ]
Kane, Lesley A. [1 ]
机构
[1] Denali Therapeut Inc, South San Francisco, CA 94080 USA
[2] Intellia Therapeut Inc, 40 Erie St, Cambridge, MA 02139 USA
[3] Odyssey Therapeut, 4242 Campus Point Ct, San Diego, CA 92121 USA
[4] BioArct, Warfvinges Vag 35, S-11251 Stockholm, Sweden
关键词
NAD(+) CLEAVAGE ACTIVITY; WALLERIAN DEGENERATION; AXON DEGENERATION; CELL-DEATH; INJURY; DISTINCT; ALPHA; ACTIVATION; SYNAPSES; REQUIRES;
D O I
10.1016/j.jbc.2024.105630
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
Sterile alpha and toll/interleukin receptor motif-containing 1 (SARM1) is a critical regulator of axon degeneration that acts through hydrolysis of NAD+ following injury. Recent work has defined the mechanisms underlying SARM1's catalytic activity and advanced our understanding of SARM1 function in axons, yet the role of SARM1 signaling in other compartments of neurons is still not well understood. Here, we show in cultured hippocampal neurons that endogenous SARM1 is present in axons, dendrites, and cell bodies and that direct activation of SARM1 by the neurotoxin Vacor causes not just axon degeneration, but degeneration of all neuronal compartments. In contrast to the axon degeneration pathway defined in dorsal tion in vitro is not sensitive to inhibition of calpain proteases. Dendrite degeneration downstream of SARM1 in hippocampal neurons is dependent on calpain 2, a calpain protease isotype enriched in dendrites in this cell type. In summary, these data indicate SARM1 plays a critical role in neurodegeneration outside of axons and elucidates divergent pathways leading to degeneration in hippocampal axons and dendrites.
引用
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页数:15
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