TY - JOUR
T1 - Disease modeling with human neurons reveals lmnb1 dysregulation underlying dyt1 dystonia
AU - Ding, Baojin
AU - Tang, Yu
AU - Ma, Shuaipeng
AU - Akter, Masuma
AU - Liu, Meng-Lu
AU - Zang, Tong
AU - Zhang, Chun Li
N1 - Funding Information:
This work was supported by The Welch Foundation Grant I-1724, Texas Alzheimer’s Research Consortium (TARCC), The Decherd Foundation, The Pape Adams Foundation, the Kent Waldrep Foundation Center for Basic Research on Nerve Growth and Regeneration, National Institutes of Health (NIH) Grants NS092616, NS099073, NS111776, and NS117065 (to C.-L.Z.) and NS112910 (to B.D.), Friends of the Alzheimer’s Disease Center (ADC), the NIH ADC Grant NIH/ NIA P30-12300-21 (to B.D.), the Department of Defense Peer Reviewed Medical Research Program (PRMRP) Grant W81XWH2010186 (to B.D.), the National Natural Sciences Foundation of China Grant No. 81801200 (to Y.T.), and the Hunan Provincial Natural Science Foundation of China Grant No. 2019JJ40476 (to Y.T.). We thank members of the Zhang laboratory (Xiaoling Zhong, Wenjiao Tai, Leilei Wang, Yunjia Zhang, and Yuhua Zou) and the Ding laboratory (Masood Sepehrimanesh, Haochen Cui, and Jacob A. Stagray) for technical help and Dr. William T. Dauer (University of Texas Southwestern) for discussion. We also thank the support from the University of Texas Southwestern Electron Microscopy Core and the Microscopy Center at the University of Louisiana at Lafayette.
Publisher Copyright:
© 2021 Society for Neuroscience. All rights reserved.
PY - 2021/3/3
Y1 - 2021/3/3
N2 - DYT1 dystonia is a hereditary neurologic movement disorder characterized by uncontrollable muscle contractions. It is caused by a heterozygous mutation in Torsin A (TOR1A), a gene encoding a membrane-embedded ATPase. While animal models provide insights into disease mechanisms, significant species-dependent differences exist since animals with the identical heterozygous mutation fail to show pathology. Here, we model DYT1 by using human patient-specific cholinergic motor neurons (MNs) that are generated through either direct conversion of patients' skin fibroblasts or differentiation of induced pluripotent stem cells (iPSCs). These human MNs with the heterozygous TOR1A mutation show reduced neurite length and branches, markedly thickened nuclear lamina, disrupted nuclear morphology, and impaired nucleocytoplasmic transport (NCT) of mRNAs and proteins, whereas they lack the perinuclear "blebs" that are often observed in animal models. Furthermore, we uncover that the nuclear lamina protein LMNB1 is upregulated in DYT1 cells and exhibits abnormal subcellular distribution in a cholinergic MNs-specific manner. Such dysregulation of LMNB1 can be recapitulated by either ectopic expression of the mutant TOR1A gene or shRNA-mediated downregulation of endogenous TOR1A in healthy control MNs. Interestingly, downregulation of LMNB1 can largely ameliorate all the cellular defects in DYT1 MNs. These results reveal the value of disease modeling with human patient-specific neurons and indicate that dysregulation of LMNB1, a crucial component of the nuclear lamina, may constitute a major molecular mechanism underlying DYT1 pathology.
AB - DYT1 dystonia is a hereditary neurologic movement disorder characterized by uncontrollable muscle contractions. It is caused by a heterozygous mutation in Torsin A (TOR1A), a gene encoding a membrane-embedded ATPase. While animal models provide insights into disease mechanisms, significant species-dependent differences exist since animals with the identical heterozygous mutation fail to show pathology. Here, we model DYT1 by using human patient-specific cholinergic motor neurons (MNs) that are generated through either direct conversion of patients' skin fibroblasts or differentiation of induced pluripotent stem cells (iPSCs). These human MNs with the heterozygous TOR1A mutation show reduced neurite length and branches, markedly thickened nuclear lamina, disrupted nuclear morphology, and impaired nucleocytoplasmic transport (NCT) of mRNAs and proteins, whereas they lack the perinuclear "blebs" that are often observed in animal models. Furthermore, we uncover that the nuclear lamina protein LMNB1 is upregulated in DYT1 cells and exhibits abnormal subcellular distribution in a cholinergic MNs-specific manner. Such dysregulation of LMNB1 can be recapitulated by either ectopic expression of the mutant TOR1A gene or shRNA-mediated downregulation of endogenous TOR1A in healthy control MNs. Interestingly, downregulation of LMNB1 can largely ameliorate all the cellular defects in DYT1 MNs. These results reveal the value of disease modeling with human patient-specific neurons and indicate that dysregulation of LMNB1, a crucial component of the nuclear lamina, may constitute a major molecular mechanism underlying DYT1 pathology.
KW - Cholinergic motor neurons
KW - Dystonia
KW - Human neurons
KW - Nuclear lmnb1
KW - Nucleocytoplasmic transport
KW - Tor1a
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UR - http://www.scopus.com/inward/citedby.url?scp=85102602883&partnerID=8YFLogxK
U2 - 10.1523/JNEUROSCI.2507-20.2020
DO - 10.1523/JNEUROSCI.2507-20.2020
M3 - Article
C2 - 33468570
AN - SCOPUS:85102602883
SN - 0270-6474
VL - 41
SP - 2024
EP - 2038
JO - Journal of Neuroscience
JF - Journal of Neuroscience
IS - 9
ER -