Speaker
Description
ALS is a neurodegenerative disease driven by proteotoxic stress. Many ALS-associated mutations affect aggrephagy, a selective autophagy pathway that clears protein aggregates \cite{ling_converging_2013}. The mTOR pathway is a bulk autophagy regulator and a potential therapeutic target.
We identified, through literature analysis, a link between p62, an aggrephagy receptor and an ALS-associated protein, and mTOR signaling, providing a mechanistic explanation for mTOR-dependent autophagy activation under proteotoxic stress \cite{duran_p62_2011}. This interaction was modeled using a parsimonious ODE system with four equations and thirteen parameters, describing the dynamics of p62 mRNA and protein, toxic aggregate mass, and aggregate-bound p62, with mTOR activity represented as a state-dependent variable. A biologically plausible parameterization was proposed, and the system’s qualitative behavior was explored as a function of the proteotoxic stress parameter S.
The model reproduces distinct dynamical regimes, such as a low-stress steady state with negligible autophagy and a high-stress regime with persistent p62-bound aggregates (consistent with ALS pathology). Moreover, two Hopf bifurcations guarantee the existence of a periodic solution at intermediate stress values. Such periodic behavior, previously reported in bulk autophagy, can be protective towards apoptosis \cite{holczer_fine-tuning_2020}. Experimental validation is needed to assess oscillatory behavior in aggrephagy.
Bibliography
@article{ling_converging_2013,
title = {Converging {Mechanisms} in {ALS} and {FTD}: {Disrupted} {RNA} and {Protein} {Homeostasis}},
volume = {79},
issn = {08966273},
shorttitle = {Converging {Mechanisms} in {ALS} and {FTD}},
doi = {10.1016/j.neuron.2013.07.033},
number = {3},
journal = {Neuron},
author = {Ling, Shuo-Chien and Polymenidou, Magdalini and Cleveland, Don W.},
month = aug,
year = {2013},
pages = {416--438},
}
@article{duran_p62_2011,
title = {p62 {Is} a {Key} {Regulator} of {Nutrient} {Sensing} in the {mTORC1} {Pathway}},
volume = {44},
issn = {10972765},
doi = {10.1016/j.molcel.2011.06.038},
number = {1},
journal = {Molecular Cell},
author = {Duran, Angeles and Amanchy, Ramars and Linares, Juan F. and Joshi, Jayashree and Abu-Baker, Shadi and Porollo, Aleksey and Hansen, Malene and Moscat, Jorge and Diaz-Meco, Maria T.},
month = oct,
year = {2011},
pages = {134--146},
}
@article{holczer_fine-tuning_2020,
title = {Fine-tuning of {AMPK}–{ULK1}–{mTORC1} regulatory triangle is crucial for autophagy oscillation},
volume = {10},
issn = {2045-2322},
doi = {10.1038/s41598-020-75030-8},
number = {1},
journal = {Scientific Reports},
author = {Holczer, Marianna and Hajdú, Bence and Lőrincz, Tamás and Szarka, András and Bánhegyi, Gábor and Kapuy, Orsolya},
month = oct,
year = {2020},
pages = {17803},
}
