title: Motor deficit in a Drosophila model of mucolipidosis type IV due to defective clearance of apoptotic cells.
abstract: Disruption of the Transient Receptor Potential (TRP) mucolipin 1 (TRPML1) channel results in the neurodegenerative disorder mucolipidosis type IV (MLIV), a lysosomal storage disease with severe motor impairments. The mechanisms underlying MLIV are poorly understood and there is no treatment. Here, we report a Drosophila MLIV model, which recapitulates the key disease features, including abnormal intracellular accumulation of macromolecules, motor defects, and neurodegeneration. The basis for the buildup of macromolecules was defective autophagy, which resulted in oxidative stress and impaired synaptic transmission. Late-apoptotic cells accumulated in trpml mutant brains, suggesting diminished cell clearance. The accumulation of late-apoptotic cells and motor deficits were suppressed by expression of trpml(+) in neurons, glia, or hematopoietic cells. We conclude that the neurodegeneration and motor defects result primarily from decreased clearance of apoptotic cells. Since hematopoietic cells in humans are involved in clearance of apoptotic cells, our results raise the possibility that bone marrow transplantation may limit the progression of MLIV.
authors.affiliation: Departments of Biological Chemistry and Neuroscience, Center for Sensory Biology, The Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
authors.forename: Kartik
authors.initials: K
authors.lastname: Venkatachalam
authors.forename: A Ashleigh
authors.initials: AA
authors.lastname: Long
authors.forename: Rebecca
authors.initials: R
authors.lastname: Elsaesser
authors.forename: Daria
authors.initials: D
authors.lastname: Nikolaeva
authors.forename: Kendal
authors.initials: K
authors.lastname: Broadie
authors.forename: Craig
authors.initials: C
authors.lastname: Montell
mesh_terms: D000818:Animals; D017209:Apoptosis; D004195:Disease Models, Animal; D004330:Drosophila / Q000378:metabolism*; D006801:Humans; D009081:Mucolipidoses / Q000378:metabolism*; D019636:Neurodegenerative Diseases / Q000378:metabolism; D050053:TRPM Cation Channels / Q000235:genetics / Q000378:metabolism
chemical_list: D050053:TRPM Cation Channels