Computational Model Explains How Huntington’s Protective Molecular Path Dead-Ends

Magdalena Kegel avatar

by Magdalena Kegel |

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Huntington's biomarkers

By using computational modeling, researchers have demonstrated that at the early stages of mutant huntingtin (mHtt) aggregation, a molecular feedback loop works to prevent the effects of the toxic aggregates, until a tipping point is reached.

Because the study, “Systemic study of a natural feedback loop in Huntington’s disease at the onset of neurodegeneration,” published in the journal Biosystems, used experimental data for its computational analysis, researchers believe the model mirrors reality rather well, as long as certain conditions are in place.

Despite the fact that mutant huntingtin — the culprit of Huntington’s disease — has been studied extensively, researchers are still in the dark about the molecular processes that kill neurons.

Because symptoms of Huntington’s disease most often do not appear until adulthood, there likely are processes that counteract the effects of mutant and misfolded huntingtin. But so far, it is not clear how nerve cells can stand the toxic effects for so long.

In earlier studies, the research team from the Saha Institute of Nuclear Physics in India had shown that a molecule called Grb2 helped to remove mutant huntingtin from cells through a process called autophagy  — a mechanism used by the cell to get rid of old or unwanted parts.

Grb2 is part of a molecular cascade that affects numerous cell processes. Studies have shown that when a cell signals a lack of growth, molecular changes cause an increase in the molecular pathway activity, that act to protect the cell from toxic effects of mutant huntingtin.

To better understand the molecular processes that first protect cells from the effects of mutant huntingtin, the research team fed information from their own experimental studies, exploring molecular events in lab-grown cells, as well as that of others, into advanced modeling software.

The models showed that at early stages a molecular pathway that acts to clear the cell, manages to counteract the effects of toxic huntingtin proteins. According to the study, Grb2 is part of this protective system, together with the molecules ERK and Foxd3. The problem arises when mutant huntingtin becomes too abundant.

Since huntingtin binds to Grb2, it removes it from the molecular chain of events offering the cell protection, so the mechanism for removing huntingtin is lost. At this stage, the researchers believe cells start dying.

“In HD presumably there could be many such “mini-circuits” conferring robustness and under pathological conditions, as the components of these circuits get trapped by mHtt aggregates, the overall players for homeostasis gets depleted leading to system failure. Replenishment of one or more of these components may be a clue to disease therapeutics,” the authors concluded.