ATXN1 Gene Tied to Rare Disorder Regulates Key Enzyme in Alzheimer’s

ATXN1 Gene Tied to Rare Disorder Regulates Key Enzyme in Alzheimer’s
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A gene associated with a rare balance disorder also may be involved in susceptibility to Alzheimer’s disease, a new study in mice shows.

The study, “Loss of Ataxin-1 Potentiates Alzheimer’s Pathogenesis by Elevating Cerebral BACE1 Transcription,” was published in the journal Cell.

Mutations that affect a gene’s function can be divided, broadly, into two groups: gain-of-function mutations, in which the gene does something extra it normally doesn’t; and loss-of-function mutations, in which the gene doesn’t work the way it should.

One example of a gain-of-function mutation occurs in spinocerebellar ataxia type 1, a rare neurological disorder characterized by loss of coordination and balance, which is caused by a gain-of-function mutation in the gene ATXN1which give instructions to make a protein called ataxin-1.

Interestingly, some studies have suggested that ATXN1 also may be involved in Alzheimer’s disease, but how hasn’t been clear because the gain-of-function mutation is linked with a separate disease.

“So the big question facing us was, how does a gene involved in a balance disorder somehow increase the risk for Alzheimer’s disease?” Rudolph E. Tanzi, PhD, explained in a press release. Tanzi is director of the Genetics and Aging Research Unit at Massachusetts General Hospital, and co-author of the study.

To find out, the researchers crossbred mice lacking a functional ATXN1 gene (essentially a loss-of-function mutation) with an Alzheimer’s mouse model (AD mice), generating mice that would both develop Alzheimer’s and lack ATXN1.

These mice, the researchers found, had significantly greater deposits of amyloid plaques (protein deposits that are characteristic of Alzheimer’s disease) than did AD mice with intact ATXN1. This suggested that loss-of-function of ATXN1 is actually what’s relevant for Alzheimer’s.

“The idea that the same protein will cause one neurodegenerative disease in a ‘gain’ situation, and cause vulnerability to another neurodegenerative disease in a ‘loss’ situation, is fascinating,” said Huda Y. Zoghbi, MD, another study co-author who is a professor at Baylor College of Medicine in Texas.

Mechanistically, the researchers found that lack of ataxin-1 reduces the activity of a protein complex called CIC-ETV4/5. This complex normally inhibits the transcription (when information contained within a gene is “decoded”) of another gene — BACE1 — which encodes for beta-secretase 1, an enzyme that helps amyloid plaques form. Basically, removing functional ATXN1 “turns off the brakes” on BACE1, leading to increased formation of plaques.

Understanding this system, and how it might be therapeutically exploited, “could provide a new avenue to safely stop formation of amyloid plaques and potentially prevent this disease before it causes symptoms,” Tanzi said.

Marisa holds an MS in Cellular and Molecular Pathology from the University of Pittsburgh, where she studied novel genetic drivers of ovarian cancer. She specializes in cancer biology, immunology, and genetics. Marisa began working with BioNews in 2018, and has written about science and health for SelfHacked and the Genetics Society of America. She also writes/composes musicals and coaches the University of Pittsburgh fencing club.
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Ana holds a PhD in Immunology from the University of Lisbon and worked as a postdoctoral researcher at Instituto de Medicina Molecular (iMM) in Lisbon, Portugal. She graduated with a BSc in Genetics from the University of Newcastle and received a Masters in Biomolecular Archaeology from the University of Manchester, England. After leaving the lab to pursue a career in Science Communication, she served as the Director of Science Communication at iMM.
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Marisa holds an MS in Cellular and Molecular Pathology from the University of Pittsburgh, where she studied novel genetic drivers of ovarian cancer. She specializes in cancer biology, immunology, and genetics. Marisa began working with BioNews in 2018, and has written about science and health for SelfHacked and the Genetics Society of America. She also writes/composes musicals and coaches the University of Pittsburgh fencing club.
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