Dendritic spinopathy in transgenic mice expressing ALS/dementia-linked mutant UBQLN2

George H. Gorrie, Faisal Fecto, Daniel Radzicki, Craig Weiss, Yong Shi, Hongxin Dong, Hong Zhai, Ronggen Fu, Erdong Liu, Sisi Li, Hasan Arrat, Eileen H. Bigio, John F. Disterhoft, Marco Martina, Enrico Mugnaini, Teepu Siddique*, Han Xiang Deng, David W. Russell

*Corresponding author for this work

Research output: Contribution to journalArticle

28 Citations (Scopus)

Abstract

Mutations in the gene encoding ubiquilin2 (UBQLN2) cause amyotrophic lateral sclerosis (ALS), frontotemporal type of dementia, or both. However, the molecular mechanisms are unknown. Here, we show that ALS/dementia-linked UBQLN2P497H transgenic mice develop neuronal pathology with ubiquilin2/ubiquitin/p62-positive inclusions in the brain, especially in the hippocampus, recapitulating several key pathological features of dementia observed in human patients with UBQLN2 mutations. A major feature of the ubiquilin2-related pathology in these mice, and reminiscent of human disease, is a dendritic spinopathy with protein aggregation in the dendritic spines and an associated decrease in dendritic spine density and synaptic dysfunction. Finally, we show that the protein inclusions in the dendritic spines are composed of several components of the proteasome machinery, including UbG76V-GFP, a representative ubiquitinated protein substrate that is accumulated in the transgenic mice. Our data, therefore, directly link impaired protein degradation to inclusion formation that is associated with synaptic dysfunction and cognitive deficits. These data imply a convergent molecular pathway involving synaptic protein recycling that may also be involved in other neurodegenerative disorders, with implications for development of widely applicable rational therapeutics.

Original languageEnglish (US)
Pages (from-to)14524-14529
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume111
Issue number40
DOIs
StatePublished - Oct 7 2014

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Dendritic Spines
Amyotrophic Lateral Sclerosis
Transgenic Mice
Dementia
Ubiquitinated Proteins
Pathology
Mutation
Proteins
Recycling
Proteasome Endopeptidase Complex
Ubiquitin
Neurodegenerative Diseases
Proteolysis
Hippocampus
Brain
Genes
Therapeutics

ASJC Scopus subject areas

  • General

Cite this

Gorrie, George H. ; Fecto, Faisal ; Radzicki, Daniel ; Weiss, Craig ; Shi, Yong ; Dong, Hongxin ; Zhai, Hong ; Fu, Ronggen ; Liu, Erdong ; Li, Sisi ; Arrat, Hasan ; Bigio, Eileen H. ; Disterhoft, John F. ; Martina, Marco ; Mugnaini, Enrico ; Siddique, Teepu ; Deng, Han Xiang ; Russell, David W. / Dendritic spinopathy in transgenic mice expressing ALS/dementia-linked mutant UBQLN2. In: Proceedings of the National Academy of Sciences of the United States of America. 2014 ; Vol. 111, No. 40. pp. 14524-14529.
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abstract = "Mutations in the gene encoding ubiquilin2 (UBQLN2) cause amyotrophic lateral sclerosis (ALS), frontotemporal type of dementia, or both. However, the molecular mechanisms are unknown. Here, we show that ALS/dementia-linked UBQLN2P497H transgenic mice develop neuronal pathology with ubiquilin2/ubiquitin/p62-positive inclusions in the brain, especially in the hippocampus, recapitulating several key pathological features of dementia observed in human patients with UBQLN2 mutations. A major feature of the ubiquilin2-related pathology in these mice, and reminiscent of human disease, is a dendritic spinopathy with protein aggregation in the dendritic spines and an associated decrease in dendritic spine density and synaptic dysfunction. Finally, we show that the protein inclusions in the dendritic spines are composed of several components of the proteasome machinery, including UbG76V-GFP, a representative ubiquitinated protein substrate that is accumulated in the transgenic mice. Our data, therefore, directly link impaired protein degradation to inclusion formation that is associated with synaptic dysfunction and cognitive deficits. These data imply a convergent molecular pathway involving synaptic protein recycling that may also be involved in other neurodegenerative disorders, with implications for development of widely applicable rational therapeutics.",
author = "Gorrie, {George H.} and Faisal Fecto and Daniel Radzicki and Craig Weiss and Yong Shi and Hongxin Dong and Hong Zhai and Ronggen Fu and Erdong Liu and Sisi Li and Hasan Arrat and Bigio, {Eileen H.} and Disterhoft, {John F.} and Marco Martina and Enrico Mugnaini and Teepu Siddique and Deng, {Han Xiang} and Russell, {David W.}",
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Dendritic spinopathy in transgenic mice expressing ALS/dementia-linked mutant UBQLN2. / Gorrie, George H.; Fecto, Faisal; Radzicki, Daniel; Weiss, Craig; Shi, Yong; Dong, Hongxin; Zhai, Hong; Fu, Ronggen; Liu, Erdong; Li, Sisi; Arrat, Hasan; Bigio, Eileen H.; Disterhoft, John F.; Martina, Marco; Mugnaini, Enrico; Siddique, Teepu; Deng, Han Xiang; Russell, David W.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 111, No. 40, 07.10.2014, p. 14524-14529.

Research output: Contribution to journalArticle

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T1 - Dendritic spinopathy in transgenic mice expressing ALS/dementia-linked mutant UBQLN2

AU - Gorrie, George H.

AU - Fecto, Faisal

AU - Radzicki, Daniel

AU - Weiss, Craig

AU - Shi, Yong

AU - Dong, Hongxin

AU - Zhai, Hong

AU - Fu, Ronggen

AU - Liu, Erdong

AU - Li, Sisi

AU - Arrat, Hasan

AU - Bigio, Eileen H.

AU - Disterhoft, John F.

AU - Martina, Marco

AU - Mugnaini, Enrico

AU - Siddique, Teepu

AU - Deng, Han Xiang

AU - Russell, David W.

PY - 2014/10/7

Y1 - 2014/10/7

N2 - Mutations in the gene encoding ubiquilin2 (UBQLN2) cause amyotrophic lateral sclerosis (ALS), frontotemporal type of dementia, or both. However, the molecular mechanisms are unknown. Here, we show that ALS/dementia-linked UBQLN2P497H transgenic mice develop neuronal pathology with ubiquilin2/ubiquitin/p62-positive inclusions in the brain, especially in the hippocampus, recapitulating several key pathological features of dementia observed in human patients with UBQLN2 mutations. A major feature of the ubiquilin2-related pathology in these mice, and reminiscent of human disease, is a dendritic spinopathy with protein aggregation in the dendritic spines and an associated decrease in dendritic spine density and synaptic dysfunction. Finally, we show that the protein inclusions in the dendritic spines are composed of several components of the proteasome machinery, including UbG76V-GFP, a representative ubiquitinated protein substrate that is accumulated in the transgenic mice. Our data, therefore, directly link impaired protein degradation to inclusion formation that is associated with synaptic dysfunction and cognitive deficits. These data imply a convergent molecular pathway involving synaptic protein recycling that may also be involved in other neurodegenerative disorders, with implications for development of widely applicable rational therapeutics.

AB - Mutations in the gene encoding ubiquilin2 (UBQLN2) cause amyotrophic lateral sclerosis (ALS), frontotemporal type of dementia, or both. However, the molecular mechanisms are unknown. Here, we show that ALS/dementia-linked UBQLN2P497H transgenic mice develop neuronal pathology with ubiquilin2/ubiquitin/p62-positive inclusions in the brain, especially in the hippocampus, recapitulating several key pathological features of dementia observed in human patients with UBQLN2 mutations. A major feature of the ubiquilin2-related pathology in these mice, and reminiscent of human disease, is a dendritic spinopathy with protein aggregation in the dendritic spines and an associated decrease in dendritic spine density and synaptic dysfunction. Finally, we show that the protein inclusions in the dendritic spines are composed of several components of the proteasome machinery, including UbG76V-GFP, a representative ubiquitinated protein substrate that is accumulated in the transgenic mice. Our data, therefore, directly link impaired protein degradation to inclusion formation that is associated with synaptic dysfunction and cognitive deficits. These data imply a convergent molecular pathway involving synaptic protein recycling that may also be involved in other neurodegenerative disorders, with implications for development of widely applicable rational therapeutics.

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