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Dec 8
2020

Researchers ID new way to prevent ALS-linked deficits in mice

In a new study, Packard investigator Mervyn Monteiro showed that increasing the expression of the UBQLN1 gene in a UBQLN2 mouse model of ALS/FTD helped to alleviate some of the behavioral and molecular signs of disease.

Packard scientists have identified a potential way to rescue deficits caused by an ALS-linked mutation in the UBQLN2 gene. In new a new study in Acta Neuropathologica Communications, neurobiologist Mervyn Monteiro and colleagues from the University of Maryland School of Medicine showed that increasing the expression of the UBQLN1 gene in a UBQLN2 mouse model of ALS/FTD helped to alleviate some of the behavioral and molecular signs of disease. The rescue, however, was sex-specific, as female mice did not appear to show the same benefits as males.

Mervyn Monterio is a neurobiologist with the University of Maryland School of Medicine.

Ubiquilin proteins help to regulate proteostasis by facilitating the removal of damaged and unwanted proteins from cells. Humans contain four different ubiquilin genes that are expressed differently throughout the body. Although researchers know quite a bit about ubiquilin and its functions, it’s less clear whether one ubiquilin protein can compensate for the loss or misfunction of another. In 2011, scientists first linked a mutation, known as P497S, in UBQLN2 to ALS and frontotemporal dementia (FTD). Monteiro and colleagues wanted to determine whether the overexpression of UBQLN1 in mice carrying the ALS-linked UBQLN2 mutation would reduce the cellular and physiological impacts of P497S. The researchers began by creating double transgenic mice that carried both human UBQLN1 and P497S UBQLN2. Compared to mice that carried only the P497S UBQLN2 gene, those that also carried the human UBQLN1 gene had less accumulation of pathological UBQLN2 protein in their brains and spinal cord.

Mice engineered to carry both of these human ubiquilin genes also had lower body weights than control mice and those carrying only a single human ubiquilin gene. However, the percentage reduction in body weight differed by sex, with female mice losing a higher percentage body weight at 52 weeks of age compared to males. Monteiro and colleagues also noted sex-based differences in rotarod performance. Males with both human ubiquilin genes had slower decline in rotarod performance compared to mice expressing only the mutant P497S UBQLN2 gene. This beneficial effect was not observed in females. Taken together, the results show that the overexpression of UBQLN1 benefits males more than females.

The researchers saw similar benefits at the molecular level. The overexpression of human UBQLN1 in mice reduced clumps of P497S UBQLN2 and other proteins tagged for recycling in both the brains and spinal cord of mice with both these genes. It also reduced the loss of neurons in the brains of P497S UBQLN2 mice, and in the loss of motor neurons in these animals. Monteiro and colleagues also noted a reduction in problems relating to TDP-43, a protein in which abnormalities are detected in 97% of ALS cases. Male mice with both UBQLN genes had normal muscle mass and fiber size, unlike P497S mice, which showed a 45% reduction in muscle weight. The addition of human UBQLN1 to male P497S mice also partially restored axon caliber.

Besides identifying important clues into the function of human ubiquilin genes, the authors conclude that these experiments also show the important sex-specific results of UBQLN2 rescue by UBQLN1 overexpression. Because of the dramatic decrease in body weight seen in female mice with two human UBQLN genes, any potential therapies may need to be carefully controlled to prevent untoward gender-specific outcomes.