Aurora Astudillo

Autophagy is an essential catabolic pathway that safeguards cellular and tissue homeostasis, yet the systemic consequences of its impairment in mammals remain poorly defined because complete autophagy ablation is embryonic or perinatal lethal. Here, we generate ATG4A-only mice, a model in which ATG4A is the sole remaining ATG4 protease due to combined ATG4B/C/D deletion. Through comprehensive biochemical and cellular analyses, we delineate the in vivo substrate specificity of ATG4A and demonstrate that it sustains only minimal ATG8 priming, uncovering a previously unrecognized functional asymmetry within the mammalian ATG4–ATG8 system. ATG4A-only mice exhibit a profound but incomplete whole-body autophagy deficiency that disrupts multiple organ systems and triggers a premature aging syndrome marked by increased DNA damage, systemic senescence, metabolic dysfunction, and dramatically shortened lifespan. Integrating these findings with comparisons to additional ATG4-deficient models, we show that organismal longevity scales with residual autophagic competence. Together, our work reveals how graded reductions in autophagy integrity influence tissue fitness and aging, establishing autophagic capacity as a key determinant of mammalian lifespan.

Rhabdoid meningiomas (RM) are a rare meningioma subtype with a heterogeneous clinical course which is more frequently associated with recurrence, even among tumors undergoing-complete surgical removal. Here, we retrospectively analyzed the clinical-histopathological and cytogenetic features of 29 tumors, from patients with recurrent (seven primary and 14 recurrent tumors) vs. non-recurrent RM (n = 8). Recurrent RM showed one (29%), two (29%) or three (42%) recurrences. BAP1 loss of expression was found in one third of all RM at diagnosis and increased to 100% in subsequent tumor recurrences. Despite both recurrent and non-recurrent RM shared chromosome 22 losses, non-recurrent tumors more frequently displayed extensive losses of chromosome 19p (62%) and/or 19q (50%), together with gains of chromosomes 20 and 21 (38%, respectively), whereas recurrent RM (at diagnosis) displayed more complex genotypic profiles with extensive losses of chromosomes 1p, 14q, 18p, 18q (67% each) and 21p (50%), together with focal gains at chromosome 17q22 (67%). Compared to paired primary tumors, recurrent RM samples revealed additional losses at chromosomes 16q and 19p (50% each), together with gains at chromosomes 1q and 17q in most recurrent tumors (67%, each). All deceased recurrent RM patients corresponded to women with chromosome 17q gains, although no statistical significant differences were found vs. the other RM patients.

ATG4 (autophagy related 4 cysteine peptidase); ATG4A (autophagy related 4A cysteine peptidase); ATG4B (autophagy related 4B cysteine peptidase); ATG4C (autophagy related 4C cysteine peptidase); ATG4D (autophagy related 4D cysteine peptidase); Atg8 (autophagy related 8); GABARAP (GABA type A receptor-associated protein); GABARAPL1(GABA type A receptor-associated protein like 1); GABARAPL2 (GABA type A receptor-associated protein like 2); MAP1LC3A/LC3A (microtubule associated protein 1 light chain 3 alpha); MAP1LC3B/LC3B (microtubule associated protein 1 light chain 3 beta); mATG8 (mammalian Atg8); PE (phosphatidylethanolamine); PS (phosphatydylserine); SQSTM1/p62 (sequestosome 1).