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Nov 7

New ALS mouse models more closely mimic the human disease

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Scientists have linked an ever-growing number of genetic mutations to ALS and a related disease, frontotemporal dementia (FTD).

Scientists have linked an ever-growing number of genetic mutations to ALS and a related disease, frontotemporal dementia (FTD). Understanding their contributions to ALS pathology requires translating these findings into usable animal models. Packard researcher Mervyn Monteiro (University of Maryland School of Medicine) and colleagues have created UBQLN2 mouse models of ALS-FTD that capture both the molecular pathology and the symptoms of the human disease. Their work was published November 7 in the journal PNAS.

“We need animal models for different ALS genes so that we can show how these different mutations cause disease. Understanding this will be a huge step in what we know about what causes ALS,” Monteiro said.

In 2011, scientists identified mutations in the UBQLN2 gene as the cause of ALS in some individuals. The UBQLN2 protein plays several roles in the cell, including acting as a molecular shuttle that transports misfolded proteins to the proteasome, where they are recycled. But when researchers knocked out UBQLN2 in rodents, it didn’t create any of the symptoms of ALS. Also, transgenic rodent models that were made carrying ALS-FTD-linked UBQLN2 mutations developed cognitive deficits but not motor neuron disease.

In the new study, Monteiro and colleagues describe transgenic UBQLN2 mouse models of ALS-FTD that develop both cognitive deficits and fatal motor neuron disease. They created several transgenic mouse lines expressing either wild-type (WT) or ALS-FTD mutant UBQLN2 proteins. As the mice aged, the animals expressing mutant UBQLN2 developed progressive weakness of their fore and hind limbs, and some also developed paralysis. By contrast, the mice expressing WT UBQLN2 appeared normal. Pathologic examination of the brain and spinal cord revealed an accumulation of UBQLN2-positive inclusions in the mutant mice. The mutant mice also had loss of motor neurons in the spinal cord and loss of innervation of their muscles, classic features of motor neuron disease in humans.

Nearly all cases of ALS display mislocalization of a protein called TDP-43, which is normally concentrated inside the nucleus of cells. In 97% of those with ALS, however, TDP-43 is lost from the nucleus and instead concentrates in the cytoplasm, where it forms large inclusions.  The mutant UBQLN2 mice with end-stage disease had TDP-43 inclusions in the cytoplasm, whereas WT UBQLN2 mice of equivalent age did not develop this pathology. This is an important feature of the model, Monteiro explains, because any ALS treatment that is ultimately developed will likely need to target TDP-43 pathology.

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