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}},
url = {https://linkinghub.elsevier.com/retrieve/pii/S0896627313006570},
doi = {10.1016/j.neuron.2013.07.033},
language = {en},
number = {3},
urldate = {2026-03-13},
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},
url = {https://linkinghub.elsevier.com/retrieve/pii/S1097276511007131},
doi = {10.1016/j.molcel.2011.06.038},
language = {en},
number = {1},
urldate = {2026-03-13},
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},
url = {https://www.nature.com/articles/s41598-020-75030-8},
doi = {10.1038/s41598-020-75030-8},
abstract = {Abstract
Autophagy is an intracellular digestive process, which has a crucial role in maintaining cellular homeostasis by self-eating the unnecessary and/or damaged components of the cell at various stress events. ULK1, one of the key elements of autophagy activator complex, together with the two sensors of nutrient and energy conditions, called mTORC1 and AMPK kinases, guarantee the precise function of cell response mechanism. We claim that the feedback loops of AMPK–mTORC1–ULK1 regulatory triangle determine an accurate dynamical characteristic of autophagic process upon cellular stress. By using both molecular and theoretical biological techniques, here we reveal that a delayed negative feedback loop between active AMPK and ULK1 is essential to manage a proper cellular answer after prolonged starvation or rapamycin addition. AMPK kinase quickly gets induced followed by AMPK-P-dependent ULK1 activation, whereas active ULK1 has a rapid negative effect on AMPK-P resulting in a delayed inhibition of ULK1. The AMPK-P → ULK1 ˧ AMPK-P negative feedback loop results in a periodic repeat of their activation and inactivation and an oscillatory activation of autophagy, as well. We demonstrate that the periodic induction of self-cannibalism is necessary for the proper dynamical behaviour of the control network when mTORC1 is inhibited with respect to various stress events. By computational simulations we also suggest various scenario to introduce “delay” on AMPK-P-dependent ULK1 activation (i.e. extra regulatory element in the wiring diagram or multi-phosphorylation of ULK1).},
language = {en},
number = {1},
urldate = {2026-03-13},
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},
}
