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Updated: Aug 19, 2025
Modeling Age-Associated Neurodegenerative Diseases in Caenorhabditis elegans
Published on: August 15, 2020
Chloroquine corrects enlarged lysosomes in FIG4 null cells and reduces neurodegeneration in Fig4 null mice
Guy M Lenk1, Miriam H Meisler2
1Department of Human Genetics, University of Michigan, Ann Arbor, MI 48109-5618, United States of America.
Abstract:
Loss-of-function mutations of FIG4 impair the biosynthesis of PI(3,5)P2 and are responsible for rare genetic disorders including Yunis-Varón Syndrome and Charcot-Marie-Tooth Disease Type 4 J. Cultured cells deficient in FIG4 accumulate enlarged lysosomes with hyperacidic pH, due in part to impaired regulation of lysosomal ion channels and elevated intra-lysosomal osmotic pressure. We evaluated the effects of the FDA approved drug chloroquine, which is known to reduce lysosome acidity, on FIG4 deficient cell culture and on a mouse model. Chloroquine corrected the enlarged lysosomes in FIG4 null cells. In null mice, addition of chloroquine to the drinking water slowed progression of the disorder. Growth and mobility were dramatically improved during the first month of life, and spongiform degeneration of the nervous system was reduced. The median survival of Fig4 null mice was increased from 4 weeks for untreated mutants to 8 weeks with chloroquine treatment (p < 0.009). Chloroquine thus corrects the lysosomal swelling in cultured cells and ameliorates Fig4 deficiency in vivo. The improved phenotype of mice with complete loss of Fig4 suggests that chloroquine could be beneficial FIG2 in partial loss-of-function disorders such as Charcot-Marie-Tooth Type 4 J.
Insights
Chloroquine treatment corrects enlarged lysosomes in cells lacking FIG4 and improves symptoms in a mouse model of FIG4 deficiency. This suggests chloroquine may benefit rare genetic disorders caused by FIG4 mutations.
Area of Science:
- Cell Biology
- Genetics
- Pharmacology
Background:
- Loss-of-function mutations in FIG4 disrupt phosphoinositide biosynthesis, leading to rare genetic disorders like Yunis-Varón Syndrome and Charcot-Marie-Tooth Disease Type 4 J.
- FIG4 deficiency causes enlarged, hyperacidic lysosomes due to impaired ion channel regulation and increased osmotic pressure.
Purpose of the Study:
- To investigate the therapeutic potential of chloroquine, an FDA-approved drug, in mitigating the cellular and in vivo phenotypes associated with FIG4 deficiency.
Main Methods:
- Evaluated chloroquine's effects on FIG4-deficient cell cultures.
- Administered chloroquine in drinking water to a mouse model of FIG4 deficiency.
- Assessed lysosomal morphology, pH, growth, mobility, neurological degeneration, and survival rates.
Main Results:
- Chloroquine treatment normalized enlarged lysosomes in FIG4-null cells.
- In FIG4-null mice, chloroquine slowed disease progression, significantly improving growth and mobility.
- Median survival of treated mice increased from 4 to 8 weeks, with reduced spongiform degeneration.
Conclusions:
- Chloroquine effectively corrects lysosomal abnormalities in vitro and ameliorates FIG4 deficiency phenotypes in vivo.
- The findings suggest chloroquine could be a potential therapeutic agent for complete and partial FIG4 loss-of-function disorders, including Charcot-Marie-Tooth Type 4 J.
