PT  - JOURNAL ARTICLE
AU  - Baojin Ding
AU  - Yu Tang
AU  - Shuaipeng Ma
AU  - Masuma Akter
AU  - Meng-Lu Liu
AU  - Tong Zang
AU  - Chun-Li Zhang
TI  - Disease modeling with human neurons reveals LMNB1 dysregulation underlying DYT1 dystonia
AID  - 10.1101/2020.08.11.246371
DP  - 2020 Jan 01
TA  - bioRxiv
PG  - 2020.08.11.246371
4099  - http://biorxiv.org/content/early/2020/08/12/2020.08.11.246371.short
4100  - http://biorxiv.org/content/early/2020/08/12/2020.08.11.246371.full
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.