Regulation of neuron-specific UPS and autophagy with aging
BRITTA EICKHOLT (Charité-Universitätsmedizin, Berlin)
JANINE KIRSTEIN (FMP, Jena)
Neuronal activity depends on carefully controlling protein abundance and function, especially at synapses, where the regulated turnover of proteins is essential for synaptic plasticity. Protein degradation is mainly carried out by the ubiquitin-proteasome system and autophagy. Although both systems are vital, we still do not fully understand how they are regulated in neuronal sub-compartments, particularly during aging, when damaged proteins accumulate.
The joint project of the Eickholt and Kirstein laboratories aims to uncover how these proteolytic systems are controlled and how they help maintain proteostasis at synapses, protecting them from age-related decline. By combining studies in the nematode C. elegans, mice, and cultured neurons, we can investigate these processes at multiple levels from individual molecules to whole organisms.
One focus of the project is on the ATM kinase, which is an important regulator of autophagy. We want to understand how ATM controls protein turnover at synapses with aging. In particular, we will study how ATM influences the formation of autophagosomes, how it affects the transport of autophagosomes, and how these processes change with age.
A second major goal is to understand why some neurons are more vulnerable to age-associated neurodegeneration than others. We will compare different neuron types to test the idea that a neuron’s ability to remove damaged proteins determines how resistant it is to degeneration. By measuring neuron-specific proteolytic activity and analyzing the proteome of vulnerable versus resilient neurons, we aim to identify regulators of the ubiquitin-proteasome system and autophagy.
References:
Hirsch F, Läubli N, Kelkar A, Sleiman M, Woitzat Y, Gallrein C, Gumz V, Kaur Kalsi G, Fernandez-Villegas A, Kaminski Schierle G, Kirstein J Impairment of neuronal activity occurs at the early stages of the aggregation cascade of Aβ1-42 and mutant Tau Disease Models and Mechanisms, 2026 (accepted; in press)
Gallrein C, Meyer DH, Woitzat Y, Ramirez-Ramirez V, Vuong-Brender T, Kirstein J, Schumacher B Aging clocks delineate neuron types vulnerable or resilient to neurodegeneration and identify neuroprotective interventions Nature Aging 2026 Feb 3. doi: 10.1038/s43587-026-01067-5
Kroon C, Bareesel S, Perez GA, Nagy-Herczeg D, Ranti D, Syropoulou V, Coveney S, Kirchner M, Gimber N, Bintig W, Brosig A, Braune G, Textoris-Taube K, Zolnik TA, Mertins P, Schmoranzer J, Milovanovic D, Leondaritis G, Eickholt BJ. Phosphorylation of presynaptic PLPPR3 controls synaptic vesicle release. iScience. 2025 Aug 27;28(9):113435. doi: 10.1016/j.isci.2025.113435. PMID: 41054519; PMCID: PMC12496174.
