Science (New York, N.Y.) · 2026
Short RNA chaperones promote aggregation-resistant TDP-43 conformers to mitigate neurodegeneration.
СтатьяНазвание и аннотация: Перевод пока не подготовлен
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Copley Katie E, Mauna Jocelyn C, Danielson Helen L, Chen Qizan, Ozguney Busra, Ngo Marilyn, Xie Longxin, Smirnov Ashleigh, Davis Matt, Mayne Leland, Linsenmeier Miriam, Rubien Jack D, Bergmann Cristian A, Portz Bede, Lee Bo Lim, Odeh Hana M, Lai Longsheng, Chang Yi-Wei, Hallegger Martina, Ule Jernej, Pasinelli Piera, Poon Yan, Mittal Jeetain, Fawzi Nicolas L, Black Ben E, Donnelly Christopher J, Jensen Brigid K, Shorter James
Аннотация
Aberrant aggregation of the prion-like RNA binding protein TDP-43 drives several fatal neurodegenerative proteinopathies, including amyotrophic lateral sclerosis (ALS). In this work, we define how short, specific RNAs solubilize TDP-43. These short RNAs engage and stabilize the TDP-43 RNA recognition motifs, which allosterically destabilizes a conserved helical region in the prion-like domain, thereby promoting aggregation-resistant conformers. Sequence-space mining identified short RNA chaperones with enhanced activity against TDP-43 and disease-linked variants. Enhanced short RNA chaperones mitigated aberrant TDP-43 phenotypes in optogenetic models and in ALS patient-derived and control motor neurons. In mice with cytoplasmic TDP-43 aggregation and motor neuron loss, an enhanced short RNA chaperone reduced pathological aggregation, restored TDP-43 function, and conferred neuroprotection. These results define a mechanistic and therapeutic framework for RNA-based strategies to counter TDP-43 proteinopathies.