Astrocytes, which are star-shaped cells that connect and support neurons and blood vessels in the brain, play a role in several central nervous system disorders, but little is known about the mechanisms they use to function. By delving into that mystery, scientists at the University of California, Los Angeles (UCLA) have managed to identify a strategy that could halt or reverse Huntington’s disease.
The UCLA scientists found that lowering mutant huntingtin protein (mHTT) expression in mice could reverse expressions of almost all the genetic alterations in astrocytes the research team had linked to Huntington’s. They reported the findings in the journal Science Translational Medicine.
Huntington’s is caused by mutation in the gene that codes for HTT. Previous research has shown that the accumulation of mHTT in astrocytes contributes to Huntington's in mice, whereas removing it slowed disease progression. That led some scientists to propose that certain astrocytes are neurotoxic and cause neuronal death in neurodegenerative diseases such as Huntington’s.
To find out more about astrocytes, Baljit Khakh and colleagues at UCLA examined gene and protein signatures in astrocytes in two Huntington’s mouse models as well as brain tissues from deceased Huntington’s patients and control patients. They found little evidence that neurotoxic astrocytes contribute to the disorder.
Instead, they identified 62 genes in astrocytes that were altered in both mice and humans, with most of them downregulated in the samples. According to the researchers, many of those genes were involved in calcium-dependent processes, G protein-coupled receptor and glutamate receptor signaling, and neurotransmitter regulation that help maintain essential functions related to Huntington’s symptoms.
The scientists designed zinc finger protein transcriptional repressors to reduce mHTT within astrocytes and, in a mouse model, successfully reversed 61 of the 62 alterations. By doing that, they were able to stop disease progression in the mice and repair some of the damage.
“We believe that if we are able to stop the progression of the disease in astrocytes and neurons, then we may be able to restore activity in the brain to what it was before the disease developed,” Khakh said in a statement.
Because of their key functions in the central nervous system, astrocytes have been studied in several neurological disorders. A Stanford University research team recently blocked a microRNA called miR-181a, which builds up in the brain after heart attacks and strokes, and found the method could prompt astrocytes to become neurons and help the brain recover. Last year, a team at UT Southwestern upregulated the LZK gene in astrocytes and showed it could improve recovery after brain and spinal cord injury.
Khakh’s team at UCLA believes its study shows lowering mHTT could be a strategy to remedy some loss of normal function in Huntington’s and that the molecular pathways in astrocytes could be exploited to delay disease progression. What’s more, lowering mHTT also be applied to research on astrocytes in other neurodegenerative diseases, trauma and injury, they argue.