Tag Archives: mouse

Researchers at the Luxembourg Centre for Systems Biomedicine (LCSB), of the University of Luxembourg, have successfully measured metabolic profiles, or the metabolomes, of different brain regions, and their findings could help better understand neurodegenerative diseases.

The metabolome represents all or at least a large part of the metabolites in a given tissue, and thus, it gives a snapshot of its physiology.

“Our results, obtained in the mouse, are promising”, says Manuel Buttini: “They open up new opportunities to better understand neurodegenerative diseases, such as Parkinson’s, and could offer new ways to intervene therapeutically. In addition, with the help of metabolic profiles, such as those we have measured, the efficacy of novel therapeutic interventions could be tested more efficiently than with more common approaches.” The researchers have just published their results in the American Journal of Pathology.

Neurodegenerative processes, such as those occurring in Parkinson’s disease, are characterized by pathological alterations of the brain cells: these cells lose their structure and function, a process that is accompanied by changes in their metabolism. Until now, most scientists have always focused on just one or a few aspects of the disease to better describe and understand the underlying mechanisms. By analysing the whole metabolome however, LCSB researchers have realized a more global approach: they now can analyse hundreds of biomolecules, produced by nerve cells in upper, middle, and lower brain regions of the mouse. In the process, they not only look at healthy brains, but also at brains in which neurodegeneration occurs.

Scientists at Mayo Clinic, Jacksonville, Florida, USA have created a novel mouse that exhibits the symptoms and neurodegeneration associated with the most common genetic forms of frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS), both of which are caused by a mutation in the a gene called C9ORF72. The study was published in the journal Science.

ALS destroys nerves that control essential movements, including speaking, walking, breathing and swallowing. After Alzheimer’s disease, FTD is the most common form of early onset dementia. It is characterized by changes in personality, behavior and language due to loss of neurons in the brain’s frontal and temporal lobes. Patients with mutations in the chromosome 9 open reading frame 72 (C9ORF72) gene have all or some symptoms associated with both disorders.

“Our mouse model exhibits the pathologies and symptoms of ALS and FTD seen in patients with theC9ORF72 mutation,” said the study’s lead author, Leonard Petrucelli, Ph.D., chair and Ralph and Ruth Abrams Professor of the Department of Neuroscience at Mayo Clinic, and a senior author of the study. “These mice could greatly improve our understanding of ALS and FTD and hasten the development of effective treatments.”

To create the model, Ms. Jeannie Chew, a Mayo Graduate School student and member of Dr. Petrucelli’s team, injected the brains of newborn mice with a disease-causing version of the C9ORF72 gene. As the mice aged, they became hyperactive, anxious, and antisocial, in addition to having problems with movement that mirrored patient symptoms. The brains of the mice were smaller than normal and had fewer neurons in areas that controlled the affected behaviors. The scientists also found that the mouse brains had key hallmarks of the disorders, including toxic clusters of ribonucleic acids (RNA) and TDP-43, a protein that has long been known to go awry in the majority of ALS and FTD cases.

“Finding TDP-43 in these mice was unexpected” Dr. Petrucelli said. “We don’t yet know how foci and c9RAN proteins are linked to TDP-43 abnormalities, but with our new animal model, we now have a way to find out.” Dr. Petrucelli and his team think these results are an important step in the development of therapies for these forms of ALS and FTD and other neurodegenerative disorders.

Chew et al. “C9ORF72 Repeat Expansions in Mice Cause TDP-43 Pathology, Neuronal Loss and Behavioral Deficits,” Science, May 14, 2015. DOI: 10.1126/science.aaa9344