The research in my lab is focused on developing new therapies of lysosomal storage diseases (LSDs) based on the understanding of molecular mechanisms of the pathogenesis of these diseases. These inherited metabolic conditions are caused by defects in a wide spectrum of lysosomal and a few non-lysosomal proteins resulting in accumulation of undigested substrates, resulting in dysfunction of lysosomal/endosomal system. The almost 60 different LSDs are individually rare genetic conditions, but, collectively, the incidence is approximately 1/2,000-3,000 live births. Since lysosomal/endosomal system is essential for cell homeostasis, this “inborn organelle disorders” results in multi-systemic diseases, and predominantly affecting the brain. The study LSDs allowed the discovery of several biological processes including the discovery of mannose-6-phosphate targeting system and currently gives insights into neurodegenerative mechanism in Alzheimer and Parkinson’s diseases.
In LSDs, the development of clinical symptoms usually correlates with a level of residual deficient enzyme activity. In patients with late onset forms of LSDs, a residual lysosomal activity is a result of missense mutations, which partially preserves catalytic enzyme function but mostly impairs the early folding process in the ER. These mutant lysosomal enzymes do not reach its appropriate conformation, and subsequently are directed to ER-associate degradation (ERAD) pathway, and are ultimately degraded by the ubiquitin-proteosome system. In this context, small molecule therapeutics are an attractive approach to treat LSDs. Enzyme-enhancement agents, including pharmacological chaperones (PC), are small molecules which are able to assist a mutant misfolded protein to achieve a native-like conformation in the endoplasmic reticulum (ER), allowing it to escape the ERAD pathway, and reach the lysosome. An advantage of this approach is that small molecules are much more likely to cross the blood brain barrier and reach neuronal cells, which are dramatically affected in LSDs. In addition, principles learned in treating one type of LSD can be applied not only to other LSDs, but also to other misconformation protein diseases, which is also feature of common neurodegenerative conditions.
- Jang D, Ye W, Tian G, Solomon M, Southall N, Hu X, Marugan J, Ferrer M, Maegawa G. Cell-based High-throughput Screen identifies GALC Enhancers as Potential Small Molecules Therapies for Krabbe Disease. Accepted to J Neurosci Res
- Klionsky DJ, Abdelmohsen K, Abe A, Abedin MJ, Abeliovich H, Acevedo Arozena A et al. Maegawa G, at al. Zughaier SM. Guidelines for the use and interpretation of assays for monitoring autophagy (3rd edition). Autophagy. 2016 Jan 2;12(1):1-222.
- Goker-Alpan O, Gambello MJ, Maegawa GHB, Nedd KJ, Gruskin DJ, Blankstein L, Weinreb NJ. Reduction of plasma globotriaosylsphingosine levels after switching from agalsidase alfa to agalsidase beta as enzyme replacement therapy for Fabry disease. J Inherit Metabol Dis. 2015 Aug 25. [Epub ahead of print].
- Kano SI, Yuan M, Cardarelli RA, Maegawa G, Higurashi N, Gaval-Cruz M, Wilson AM, Tristan C, Kondo MA, Chen Y, Koga M, Obie C, Ishizuka K, Seshadri S, Srivastava R, Kato TA, Horiuchi Y, Sedlak TW, Lee Y, Rapoport JL, Hirose S, Okano H, Valle D, O’Donnell P, Sawa A, Kai M. Clinical utility of neuronal cells directly converted from fibroblasts of patients for neuropsychiatric disorders: studies of lysosomal storage diseases and channelopathy. Current Molecular Medicine 2015;15(2):138-45.
- Teixeira CA, Miranda CO, Sousa MM, Santos TE, Malheiro AR, Solomon M, Maegawa GH, Brites P, Sousa MM. Early axonal loss accompanied by impaired endocytosis, abnormal axonal transport, and decreased microtubule stability occur in the model of Krabbe’s disease. Neurobiol Dis. 2014 Jun;66:92-103.
- Ribbens J, Moser AB, Hubbard W, Bongarzone E, Maegawa GHB. A novel disease-cell model for a neurodegenerative lysosomal disease with pathogenic and therapeutic implications. Mol Genet Metab. 2014 Feb;111(2):172-83.
- Patil SA, Maegawa GH. Developing therapeutic approaches for metachromatic leukodystrophy. Drug Des Devel Ther. 2013 Aug 8;7:729-45.
- Ribbens J, Whiteley G, Furuya H, Southall N, Hu X, Marugan J, Ferrer M, Maegawa GH. A high-throughput screening assay using Krabbe disease patient cells. Anal Biochem. 2013 Mar 1;434(1):15-25.
- Geng H, Whiteley G, Ribbens J, Zheng W, Southall N, Hu X, Marugan JJ, Ferrer M, Maegawa GHB. Novel Patient Cell-Based HTS Assay for Identification of Small Molecules for a Lysosomal Storage Disease. PLoS One. 2011;6(12):e29504.
- Maegawa GHB, Tropak M, Buttner JD, Rigat B, Fuller M, Pandit D, Tang L, Kornhaber GJ, Hamuro Y, Clarke JTR, Mahuran DJ. Identification and characterization of ambroxol as an enzyme-enhancement agent for Gaucher disease. J Biol Chem 2009;284(35):23502-16
- Maegawa GH, Tropak M, Butner J, Stockley T, Kok F, Clarke JTR, Mahuran DJ. Pyrimethamine as a potential pharmacological chaperone for late-onset forms of GM2 gangliosidosis. J Biol Chem. 2007, 82(12): 9150-9161.
- Maegawa GHB, Banwell B, Blaser S, Hawkins C, Arckerley C, Hayes J, Tlopak M, Sorge G, Clarke Substrate reduction therapy in juvenile GM2 gangliosidosis. Mol Genet Metab. 2009;98(1-2):215-24.