SpectraSage unveils specific proteolytic patterns of 20S on mono-ubiquitylated Tau proteoforms involved in neurodegeneration
Abstract
, age-related macular degeneration, glaucoma). A common feature of neurodegeneration is the progressive accumulation of amyloidogenic proteins such as beta-amyloid and tau protein (MAPT gene). There is compelling evidence that the aggregation propensity of tau protein is regulated by post-synthetic modifications including phosphorylation and ubiquitylation. These alterations are gaining increasing pathological relevance not only for brain tauopathies but also for the retinal/optic nerve degenerative diseases. In this regard, site-specific mono-ubiquitylated (Ub) tau proteoforms, have been recently identified in neurodegenerative brains. In this work, the cleavage patterns of the uncapped 20S proteasome acting on mono-Ub regio-isomers of tauK18, which covers the 4RD domain, have been unveiled by using SpectraSage, a novel proteomics software conceived for the MS1 identification of complex branched peptide and here introduced for the first time. Ub position was found to affect regio-isomers susceptibility to proteolysis and unexpectedly long Ub-tauK18 branched peptides have been identified, proving distinct catalytic preferences. These findings show that the 20S digests mono-Ub proteins through specific enzymatic mechanisms and the implications of the latter on neurodegeneration are discussed.
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BibTeX
@article{zingale2026spectrasage,
title = {{SpectraSage unveils specific proteolytic patterns of 20S on mono-ubiquitylated Tau proteoforms involved in neurodegeneration}},
author = {Gabriele Antonio Zingale and Irene Pandino and Daniele Trivellato and Dario Cavaterra and Francesca Munari and Giuseppe Grasso and Peter Bell and Francesco Oddone and Alessio Bocedi and Massimiliano Coletta and Michael Assfalg and Mariapina d'Onofrio and Grazia Raffaella Tundo and Diego Sbardella},
journal = {Chemical Science},
year = {2026},
month = oct,
doi = {10.1039/d5sc04240b},
url = {https://hal.science/hal-05782945v1},
note = {CC BY-NC},
}
RIS
TY - JOUR
TI - SpectraSage unveils specific proteolytic patterns of 20S on mono-ubiquitylated Tau proteoforms involved in neurodegeneration
AU - Gabriele Antonio Zingale
AU - Irene Pandino
AU - Daniele Trivellato
AU - Dario Cavaterra
AU - Francesca Munari
AU - Giuseppe Grasso
AU - Peter Bell
AU - Francesco Oddone
AU - Alessio Bocedi
AU - Massimiliano Coletta
AU - Michael Assfalg
AU - Mariapina d'Onofrio
AU - Grazia Raffaella Tundo
AU - Diego Sbardella
PY - 2026
DA - 2026/10/07
JO - Chemical Science
DO - 10.1039/d5sc04240b
UR - https://hal.science/hal-05782945v1
AB - , age-related macular degeneration, glaucoma). A common feature of neurodegeneration is the progressive accumulation of amyloidogenic proteins such as beta-amyloid and tau protein (MAPT gene). There is compelling evidence that the aggregation propensity of tau protein is regulated by post-synthetic modifications including phosphorylation and ubiquitylation. These alterations are gaining increasing pathological relevance not only for brain tauopathies but also for the retinal/optic nerve degenerative diseases. In this regard, site-specific mono-ubiquitylated (Ub) tau proteoforms, have been recently identified in neurodegenerative brains. In this work, the cleavage patterns of the uncapped 20S proteasome acting on mono-Ub regio-isomers of tauK18, which covers the 4RD domain, have been unveiled by using SpectraSage, a novel proteomics software conceived for the MS1 identification of complex branched peptide and here introduced for the first time. Ub position was found to affect regio-isomers susceptibility to proteolysis and unexpectedly long Ub-tauK18 branched peptides have been identified, proving distinct catalytic preferences. These findings show that the 20S digests mono-Ub proteins through specific enzymatic mechanisms and the implications of the latter on neurodegeneration are discussed.
SN - 2041-6520
SN - 2041-6539
ER -