INVESTIGATING MICROGLIAL FUNCTION ACROSS LYSOSOMAL STORAGE DISORDERS

Lysosomal Storage Disorders (LSDs) are inherited metabolic diseases characterized by toxic material buildup inside the lysosomes of the cell. There are numerous LSDs, but the most common ones include Neuronal Ceroid Lipofuscinosis type 3 (NCL3 is a genetic knockout of a lysosomal transmembrane transport channel, CLN3), NCL2 (a mutation of the lysosomal enzyme Tripeptidyl peptidase 1 [TPP1], detrimental to the breakdown of storage material), and Mucolipidosis type IV (a genetic knockout of a lysosomal Ca2+ permeable membrane protein channel, mucolipin-1 [TRPML1]). Common symptoms appear at about 4 to 5 years of age, manifesting in neuropathological symptoms, including seizures and neurocognitive decline, leading to premature death. Recent studies have demonstrated that the activation of the lysosomal ion channel TRPML1 can be beneficial in several neurodegenerative disease models, such as NCL3, linking these two protein channels in a yet unknown way. The goal of this study was to obtain more knowledge about the function of TRPML1 knockout microglial cells and to assess neuroinflammatory phenotypes across the LSD mouse models. Several organelle immunostainings and phagocytotic functional assays were successfully created to evaluate the role of microglial cells in these disease models. We have identified various common phenotypes shared across these LSDs, including abnormal mitochondrial, golgi, and endoplasmic reticulum morphology, increased SubC formation, enlarged lysosomal vesicles, and abnormal autophagosome accumulation. Future outlooks involve developing disease-relevant models that will help us understand the mechanisms of these proteins in neuroinflammation pathways and perform more lipidomic and proteomic assays to gain more insight into the role of the proteins in lysosomal function and lipid metabolism.

For more information: Jrromley@eckerd.edu 

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