Disruption of the nuclear membrane by perinuclear inclusions of mutant huntingtin causes cell-cycle re-entry and striatal cell death in mouse and cell models of Huntington's disease.
Accumulation of N-terminal fragments of mutant huntingtin (mHTT) in the cytoplasm, nuclei and axons of neurons is a hallmark of Huntington's disease (HD), although how these fragments negatively impact neurons remains unclear. We followed the distribution of mHTT in the striata of transgenic R6/2-J2 HD mice as their motor function declined. The fraction of cells with diffuse, perinuclear or intranuclear mHTT changed in parallel with decreasing motor function. In transgenic mice, medium spiny neurons (MSNs) that exhibited perinuclear inclusions expressed cell-cycle markers typically not seen in the striata of normal mice, and these cells are preferentially lost as disease progresses. Electron microscopy reveals that perinuclear inclusions disrupt the nuclear envelope. The progression of perinuclear inclusions being accompanied by cell-cycle activation and culminating in cell death was also observed in 1° cortical neurons. These observations provide a strong correlation between the subcellular location of mHTT, disruption of the nucleus, re-entry into the cell-cycle and eventual neuronal death. They also highlight the fact that the subcellular distribution of mHTT is highly dynamic such that the distribution of mHTT observed depends greatly on the stage of the disease being examined.
Department of Life Sciences and Institute of Genome Sciences and Institute of Molecular Biology and.
Kuan-Yu
KY
Liu
VYM Genome Research Center, National Yang-Ming University, Taipei 112, Taiwan, Institute of Molecular Biology and.
Yu-Chiau
YC
Shyu
Developmental Biology Center, Department of Developmental and Cell Biology.
Brett A
BA
Barbaro
Institute of Molecular Biology and.
Yuan-Ta
YT
Lin
Institute of Biomedical Sciences, Academia Sinica, Nankang, Taipei 115, Taiwan, ROC.
Yijuang
Y
Chern
Department of Psychiatry and Human Behavior, Department of Neurobiology and Behavior, University of California, Irvine, CA 92697, USA.
Leslie Michels
LM
Thompson
Department of Life Sciences and Institute of Genome Sciences and Institute of Molecular Biology and jlmarsh@uci.edu ckshen@imb.sinica.edu.tw.
Che-Kun
CK
James Shen
Developmental Biology Center, Department of Developmental and Cell Biology jlmarsh@uci.edu ckshen@imb.sinica.edu.tw.
J Lawrence
JL
Marsh
D000818:Animals; D002453:Cell Cycle; D016923:Cell Death; D003342:Corpus Striatum / Q000166:cytology / Q000648:ultrastructure*; D004195:Disease Models, Animal; D006801:Humans; D000071058:Huntingtin Protein; D006816:Huntington Disease / Q000235:genetics / Q000473:pathology*; D002479:Inclusion Bodies / Q000648:ultrastructure*; D051379:Mice; D008822:Mice, Transgenic; D009154:Mutation; D009419:Nerve Tissue Proteins / Q000235:genetics*; D009474:Neurons / Q000166:cytology / Q000648:ultrastructure*; D009685:Nuclear Envelope / Q000648:ultrastructure*
C086055:HTT protein, human; D000071058:Huntingtin Protein; D009419:Nerve Tissue Proteins