Mutations in the UBQLN2 gene, which encodes the ubiquitin-like protein ubiquilin2 (UBQLN2) have been shown to cause ALS and ALS/dementia. Ubiquilin2 links familial and sporadic forms of the disease through pathology observed in the spinal cords of all ALS cases and in the brains of ALS/dementia cases with or without UBQLN2 mutations. In this communication, we develop and characterize a mouse model of mutant UBQLN2-linked dementia. We demonstrate that mutant mice develop impairment in the protein degradation pathway, abnormal protein aggregation, synaptic dysfunction, and cognitive deficits. This model provides a useful tool to further study dementia and develop rational therapies.

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.