RT Journal Article
SR Electronic
T1 Disease modeling with human neurons reveals LMNB1 dysregulation underlying DYT1 dystonia
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 2020.08.11.246371
DO 10.1101/2020.08.11.246371
A1 Baojin Ding
A1 Yu Tang
A1 Shuaipeng Ma
A1 Masuma Akter
A1 Meng-Lu Liu
A1 Tong Zang
A1 Chun-Li Zhang
YR 2020
UL http://biorxiv.org/content/early/2020/08/12/2020.08.11.246371.abstract
AB DYT1 dystonia is a hereditary neurological disease caused by a heterozygous mutation in torsin A (TOR1A). While animal models provide insights into disease mechanisms, significant species-dependent differences exist since mice with the identical heterozygous mutation fail to show pathology. Here, we model DYT1 by using human patient-derived motor neurons. These neurons with the heterozygous TOR1A mutation show markedly thickened nuclear lamina, disrupted nuclear morphology, and impaired nucleocytoplasmic transport, whereas they lack the perinuclear “blebs” that are often observed in animal models. Importantly, we further uncover that the nuclear lamina protein LMNB1 is specifically dysregulated in expression and subcellular localization. LMNB1 downregulation can largely ameliorate all the cellular defects in DYT1 motor neurons. These results reveal the value of disease modeling with human neurons and provide novel molecular mechanisms underlying DYT1 dystonia and potentially other neurological diseases with impaired nucleocytoplasmic transport.Competing Interest StatementThe authors have declared no competing interest.