Neurodegeneration

Autophagy in Neurodegeneration

We have previously identified that multiple pathogenic proteins related with Parkinson’s disease (PD) and Alzheimer’s disease (AD) exert a toxic effect on autophagic pathways including CMA and eMI. We have now confirmed this toxicity in vivo using a novel fluorescent CMA reporter mouse model crossed with a model of PD. Our current efforts focus on identifying the consequences of that toxicity and whether it can be prevented. We have found that reduced CMA accelerates disease progression and propagation in mouse models of frontotemporal dementia and are currently using genetic and chemical approaches in both PD and AD models to determine if activation of CMA could slow disease progression.

  • Chaperone-mediated autophagy prevents collapse of the neuronal metastable proteome. Bourdenx M, Martin-Segura A, Scrivo A, Rodriguez-Navarro J, Kaushik S, Tasset I, Diaz A, Strom NJ, Xin Q, Juste YR, Stevenson E, Luengo E, Clement C, Choi SJ, Krogan NJ, Mosharov EV, Santambrogio L, Grueninger F, Collin L, Swaney DL, Sulzer D, Gavathiotis E, Cuervo AM. Cell, 2021. doi: 10.1016/j.cell.2021.03.048

  • Acetylated tau inhibits chaperone-mediated autophagy and promotes tau pathology propagation in mice. Caballero B, Bourdenx M, Luengo Martin E, Diaz A, Sohn PD, Chen X, Wang C, Wegman S, Patel B, Young ZT, Kuo SY, Rodriguez-Navarro JA, Shao H, Karch CM, Goate A, Gesticki JE, Hyman BT, Gan L, Cuervo AM. Nat Comm, 2021. doi: 10.1038/s41467-021-22501

  • Selective autophagy as a potential therapeutic target for neurodegenerative disorders. Scrivo A, Bourdenx M, Pampliega O, Cuervo AM. Lancet Neurol, 2018. doi: 10.1016/S1474-4422(18)30238-2

  • Interplay of pathogenic forms of human tau with different autophagic pathways. Caballero B, Wang Y, Diaz A, Tasset I, Juste YR, Mandelkow E-, Mandelkow E, Cuervo AM. Aging Cell, 2017. doi: 10.2222/acel.12692

  • Huntingtin functions as a scaffold for selective macroautophagy. Rui Y-N, Xu Z, Patel B, Chen Z, Chen D, Tito A, David G, Sun Y, Stimming EF, Bellen HJ, Cuervo AM, Zhang S. Nat Cell Biol, 2015. doi: 10.1038/ncb3101

  • Interplay of LRRK2 with chaperone-mediated autophagy. Orenstein SJ, Kuo SH, Tasset-Cuevas I, Arias E, Koga H, Fernandez-Carasa I, Cortes E, Honig LS, Dauer W, Consiglio A, Raya A, Sulzer, D, Cuervo AM. Nat Neurosci, 2013. doi: 10.1038/nn.3350