Study Finds Abnormal Neural Development May Contribute to Huntington’s Disease, Offering New Therapeutic Strategy

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by Forest Ray PhD |

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Abnormal development of neural tissues may precede neurodegeneration in early-onset juvenile forms of Huntington’s disease, a recent study has found.

Researchers also showed how targeting the cellular pathway involved in this process might be an effective strategy to restore normal neural development.

Their study, “Expanded huntingtin CAG repeats disrupt the balance between neural progenitor expansion and differentiation in human cerebral organoids,” was pre-published on bioRxiv.

The decay of healthy brain tissue is a key physiological component of Huntington’s disease, a fatal neurodegenerative disease that’s caused by mutations in the huntingtin gene (HTT) gene. The CAG repeat is present in healthy cells, but in the case of Huntington’s, it undergoes an even greater expansion, leading to neurodegeneration, or the decay in brain tissue.

Generally, 40 or more CAG repeats cause Huntington’s symptoms to appear in one’s thirties and the more repeats after that, the earlier that symptoms appear. If you think of the letters of the DNA code as the words of a sentence, the CAG repeat is like a stutter.

Researchers have thought that Huntington’s involves normal brain development, followed by a degenerative phase, during which symptoms appear. Some studies, however, have suggested that children at risk for Huntington’s show signs of abnormal brain development.

To watch how neural cells with HTT mutations develop, the authors of this study grew cerebral organoids, or three-dimensional cell cultures of brain tissue, out of two types of stem cells containing varying lengths of CAG repeats. For this experiment, they used both embryonic stem cells with HTT mutations and induced pluripotent stem cells derived from Huntington’s patients.

Organoids better represent the complex environments of real organs than, for instance, cells grown in Petri dishes.

The longer the CAG repeat was, the less the cells were able to form organoids and the faster they reached their final stage of specialization. Premature specialization, or differentiation, results in less cell growth and therefore abortive organ development. In this case, the altered growth and development happened because the longer CAG repeats changed the timing of cell division.

With cell growth and division so well studied, the group quickly identified an important cell cycle regulator protein called ATM, which became more active in HTT mutant cells. ATM is a key player in the ATM-p53 pathway, an important regulator of the cell cycle and therefore of cellular proliferation and development.

Because that pathway is well-known and highly studied, scientists have ways of targeting specific components within it, including ATM.

The researchers partially reversed the blunted neural development seen in the organoids by treating those cells with a compound that dialed down ATM activity. This resulted in better neural growth features and points towards a potential future therapeutic avenue.

Overall, this study challenges the belief that Huntington’s is a purely neurodegenerative disease. If altered brain development does, in fact, contribute to the disease, then efforts to treat Huntington’s would benefit from an even earlier start.

Reversing the abnormal brain development early on could prove an effective treatment or even prevent the disease from occurring, the researchers said.