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Peer-Reviewed Publication
Nat Cell Biol2025;27(10):1688-1707.October 1, 2025Journal Article

Chaperone-mediated autophagy regulates neuronal activity by sex-specific remodelling of the synaptic proteome.

Rabia R Khawaja1,2, Ernesto Griego3, Kristen Lindenau4,5, Asma Salek3, Jessica Gambardella6, Aurora Scrivo4,5,7, Hannah R Monday3,8, Mathieu Bourdenx4,5,9, Jesús Madero-Pérez10,11, Zohaib N Khan12, Bhakti Chavda4,5, Ronald Cutler5,13, Sarah Graff13, Simone Sidoli13, Gaetano Santulli5,6, Laura Santambrogio12, Inmaculada Tasset4,5,14, Susmita Kaushik4,5, Li Gan10, Pablo E Castillo15,16, Ana Maria Cuervo17,18
1Department of Developmental and Molecular Biology, Albert Einstein College of Medicine, Bronx, NY, USA. rabia.khawaja@einsteinmed.edu.
2Institute for Aging Research, Department of Medicine, Albert Einstein College of Medicine, Bronx, NY, USA. rabia.khawaja@einsteinmed.edu.
3Dominick P. Purpura Department of Neuroscience, Albert Einstein College of Medicine, Bronx, NY, USA.
4Department of Developmental and Molecular Biology, Albert Einstein College of Medicine, Bronx, NY, USA.
5Institute for Aging Research, Department of Medicine, Albert Einstein College of Medicine, Bronx, NY, USA.
6Fleischer Institute for Diabetes and Metabolism (FIDAM) and Wilf Family Cardiovascular Research Institute, Department of Molecular Pharmacology, Albert Einstein College of Medicine, Bronx, NY, USA.
7Bellvitge Biomedical Research Institute (IDIBELL), University of Barcelona, Barcelona, Spain.
8Helen Wills Neuroscience Institute, University of California, Berkeley, CA, USA.
9UK Dementia Research Institute, University College London, London, UK.
10Helen and Robert Appel Alzheimer's Disease Research Institute, Brain and Mind Research Institute, Weill Cornell Medicine, New York, NY, USA.
11Verge Genomics, South San Francisco, CA, USA.
12Department of Radiation Oncology, Weill Cornell Medicine, New York, NY, USA.
13Department of Biochemistry, Albert Einstein College of Medicine, Bronx, NY, USA.
14Department of Biochemistry and Molecular Biology, University of Córdoba, Córdoba, Spain.
15Dominick P. Purpura Department of Neuroscience, Albert Einstein College of Medicine, Bronx, NY, USA. pablo.castillo@einsteinmed.edu.
16Department of Psychiatry and Behavioral Sciences, Albert Einstein College of Medicine, Bronx, NY, USA. pablo.castillo@einsteinmed.edu.
17Department of Developmental and Molecular Biology, Albert Einstein College of Medicine, Bronx, NY, USA. ana-maria.cuervo@einsteinmed.edu.
18Institute for Aging Research, Department of Medicine, Albert Einstein College of Medicine, Bronx, NY, USA. ana-maria.cuervo@einsteinmed.edu.
PubMed DOI

Abstract

Chaperone-mediated autophagy (CMA) declines in ageing and neurodegenerative diseases. Loss of CMA in neurons leads to neurodegeneration and behavioural changes in mice but the role of CMA in neuronal physiology is largely unknown. Here we show that CMA deficiency causes neuronal hyperactivity, increased seizure susceptibility and disrupted calcium homeostasis. Pre-synaptic neurotransmitter release…

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