Autophagy Guided Interventions to Modify the Cardiac Phenotype of Danon Disease

Authors

Dor Yadin, Felsenstein Research Center and the Department of Cardiothoracic, Rabin Medical Center, Sackler School of Medicine, Tel-Aviv University, Petach Tikva, Israel; Leviev Heart Center, Sheba Medical Center, Sackler School of Medicine, Tel-Aviv University, Israel.
Zachary Petrover, Felsenstein Research Center and the Department of Cardiothoracic, Rabin Medical Center, Sackler School of Medicine, Tel-Aviv University, Petach Tikva, Israel; Bar-Ilan University, Ramat Gan, Israel.
Asher Shainberg, Bar-Ilan University, Ramat Gan, Israel.
Ronny Alcalai, Heart Institute, Hadassah Hebrew University Medical Center, Jerusalem, Israel.
Maayan Waldman, Felsenstein Research Center and the Department of Cardiothoracic, Rabin Medical Center, Sackler School of Medicine, Tel-Aviv University, Petach Tikva, Israel.
Jon Seidman, Department of Genetics, Harvard Medical School, Boston, MA, USA.
Christine E. Seidman, Department of Genetics, Harvard Medical School, Boston, MA, USA; Howard Hughes Medical Institute and Cardiovascular Division, Brigham and Women's Hospital, Boston, MA 02115, United States.
Nader G. Abraham, Departments of Medicine and Pharmacology, New York Medical College, Valhalla, NY, USA.Follow
Edith Hochhauser, Felsenstein Research Center and the Department of Cardiothoracic, Rabin Medical Center, Sackler School of Medicine, Tel-Aviv University, Petach Tikva, Israel.
Michael Arad, Leviev Heart Center, Sheba Medical Center, Sackler School of Medicine, Tel-Aviv University, Israel. Electronic address: michael.arad@sheba.health.gov.il.Follow

Author Type(s)

Faculty

DOI

10.1016/j.bcp.2022.115229

Journal Title

Biochemical Pharmacology

First Page

115229

Document Type

Article

Publication Date

10-1-2022

Department

Medicine

Abstract

Danon disease is a lethal X-linked genetic syndrome resulting from radical mutations in the LAMP2 gene. LAMP2 protein deficiency results in defective lysosomal function, autophagy arrest and a multisystem disorder primarily involving the heart, skeletal muscle and the central nervous system. Cardiomyopathy is the main cause of morbidity and mortality. To investigate the mechanisms of and develop therapies for cardiac Danon disease we engineered a mouse model carrying an exon 6 deletion human mutation in LAMP2, which recapitulates the human cardiac disease phenotype. Mice develop cardiac hypertrophy followed by left ventricular dilatation and systolic dysfunction, in association with progressive fibrosis, oxidative stress, accumulation of autophagosomes and activation of proteasome. Stimulation of autophagy in Danon mice (by exercise training, caloric restriction, and rapamycin) aggravate the disease phenotype, promoting dilated cardiomyopathy. Inhibiting autophagy (by high fat diet or hydroxychloroquine) is better tolerated by Danon mice compared to wild type but is not curative. Inhibiting proteasome by Velcade was found to be highly toxic to Danon mice, suggesting that proteasome is activated to compensate for defective autophagy. In conclusion, activation of autophagy should be avoided in Danon patients. Since Danon's is a lifelong disease, we suggest that lifestyle interventions to decrease cardiac stress may be useful to slow progression of Danon's cardiomyopathy. While Danon mice better tolerate high fat diet and sedentary lifestyle, the benefit regarding cardiomyopathy in humans needs to be balanced against other health consequences of such interventions.

Recommended Citation

Yadin, D., Petrover, Z., Shainberg, A., Alcalai, R., Waldman, M., Seidman, J., Seidman, C. E., Abraham, N. G., Hochhauser, E., & Arad, M. (2022). Autophagy Guided Interventions to Modify the Cardiac Phenotype of Danon Disease. Biochemical Pharmacology, 204, 115229. https://doi.org/10.1016/j.bcp.2022.115229