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.
Bibliographical noteFunding Information:
This investigator-sponsored work was supported by a Research Support Grant from Sanofi and by Seymour Fefer Grant in Sheba Medical Center.
We are grateful to Ms. Tali Guetta for technical assistance and to Ms. Elaine Finkelstein for help with editing. This work constitutes part of Dor Yadin's PhD thesis work in Sackler School of Medicine, Tel Aviv University and Zachary Petrover's MSc project in Bar-Ilan University, Israel. This investigator-sponsored work was supported by a Research Support Grant from Sanofi and by Seymour Fefer Grant in Sheba Medical Center.
© 2022 Elsevier Inc.
- Animal model of human disease