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

Research output: Contribution to journalArticlepeer-review

56 Scopus citations


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
Issue number40
StatePublished - Oct 7 2014

ASJC Scopus subject areas

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