The ~40 lysosomal storage diseases (LSDs) account for the most common cause of neurodegeneration in young children. One of these devastating LSDs, for which there is no treatment, is mucolipidosis type IV (MLIV). Patients with MLIV are diagnosed typically at about 1-3 years of age and display severe motor function deficits, mental retardation and retinal degeneration. The defects in lysosomal activity in MLIV patients are not exclusive to the central nervous system (CNS), but are observed in most organs and tissues. The pathogenesis underlying the clinical characteristics of MLIV is not clearly understood. MLIV arises from loss-of-function mutations in the human MCOLN1 gene, which disrupt the Mucolipin1 (TRPML1) protein. TRPML1 belongs to the Transient Receptor Potential (TRP) superfamily of cation channels, which include homologs in worms (cup-5), flies (trpml) and mice (Mcoln1 or TRPML1). Mutations that disrupt the function of the TRPML1 homolog in both invertebrate models disrupt lysosomal function. Most recently, analysis of the Drosophila trpml knockout demonstrates that the progressive neurodegeneration and motor impairment result from a defect in the removal of early apoptotic neurons in the brain, which leads to accumulation of late apoptotic neurons, release of cytotoxic cellular contents and cell death in the adjacent cells. The progressive neurodegeneration, due to this bystander effect, and the ensuing motor defects are suppressed by expression of the wild-type trpml+ gene in macrophages. Here, I propose to focus on a MLIV mouse model to test concepts concerning the pathogenesis of neurodegeneration, which we have gleaned from the Drosophila model. In addition, I propose to test whether bone marrow transplantation will reduce the severity of the phenotype. This proposal is feasible since I have obtained the recently generated mouse model (TRPML1-/-) that recapitulates clinical manifestations of MLIV. Moreover, I started characterizing the TRPML1-/- mice and found that they display progressive neurodegeneration in the brain and motor defects.
Aim one is to test the hypothesis that the hematopoietic phagocytes in the TRPML1-/- mice are defective in endocytosis and lysosomal dependent degradation.
Aim two is to test the hypotheses that the TRPML1-/- knockout mice display chronic neuroinflammation, which contributes to neurotoxicity. I suggest that my proposed study will provide insight into how neuroinflammation contributes to the progression of a broad range of neurodegenerative conditions. The third and most important aim is to test the hypothesis that bone marrow transplantation in the TRPML1-/- knockout will suppress the severity of the neurodegeneration. If so, this would raise the possibility that bone marrow transplantation may be a treatment for MLIV. Finally, the findings from the proposed study on the mouse MLIV model may provide insights into the mechanisms underlying the progressive neuronal cell death that characterize a broad range of neurodegenerative diseases.

Public Health Relevance

The proposed research is aimed at understanding the cellular mechanisms that are involved in MLIV neurodegeneration. MLIV is a devastating childhood disease which lacks any treatment for the disease, I am testing BMT as a viable treatment for suppressing neurodegeneration in MLIV patients. This proposed work is relevant to the understanding and treatment of MLIV, and to improving the lives of MLIV patients.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Postdoctoral Individual National Research Service Award (F32)
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Special Emphasis Panel (ZRG1-F01-L (20))
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Morris, Jill A
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Johns Hopkins University
Schools of Medicine
United States
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