Systemic study of a natural feedback loop in Huntington's disease at the onset of neurodegeneration

Aggregation prone Huntingtin (Htt) protein and its aberrations, causing protein misfolding, have been the prototype of intense research for several decades. Misfolded aggregates or oligomers of different sizes not only deregulate the homeostasis, cellular machinery also counterbalances the effects at least at the initial stages, till the balance tilts towards toxicity and degeneration. In this paper, we combine experimental approaches with system based computational modeling to decipher the molecular mechanisms as well as the hidden dynamics leading to neuronal death in HD. We built an abstracted Boolean gate based electronic circuit that captured the available knowledge and experimental data. We inferred the unknown parameters by simultaneously fitting experimental data generated in both control and perturbed conditions. We demonstrate that, at the initial stages of Htt aggregate formation, individual changes in different protein levels and their interactions in cascade constitute the Grb2-pERK-Foxd3 feedback loop that is sufficient to create Hill-like sensitivity and prevent aggregation to the extent till mutant Htt (mHtt) aggregates become predominant in the cell when they spatially isolate the homeostatic reaction mechanism.