Lysosomal diseases represent a group of nearly 60 monogenic human disorders caused by defects in proteins involved in normal functioning of the lysosomal system. Most severely impact the brain, cause progressive neurological deterioration over years to decades, and are fatal. Pathogenic cascades caused by lysosomal dysfunction are remarkably complex and involve diverse and unusual events ranging from the blockage of autophagy to the growth of bizarre and unique (to lysosomal diseases) ?ectopic? dendrites on cortical pyramidal neurons. To provide a conceptual framework for understanding this complexity we developed in 2009 the concept of a ?Greater Lysosomal System? which put the lysosome at center stage in the cell's recycling process, receiving ?streams? of different metabolites from both endosomal and autophagosomal pathways. We also emphasized ?egress? of catabolic products from lysosomes since lack of such salvage would be anticipated to result in deficient precursors for metabolic pathways and possible up-regulation of synthesis or induction of autophagy to overcome such deficiency. Importantly, recent discoveries give credence to this concept ? most notably that a master regulator of cell metabolism, the mammalian target of rapamycin (mTOR, specifically mTORC1), is anchored at the surface of lysosomes. Here, among a myriad of functions, it controls the translocation of the MITF family of transcription factors (e.g., TFEB, TFE3) which themselves regulate hundreds of genes involved in autophagy and lysosomal biogenesis. Thus much evidence now supports the idea of the lysosome as the cell's ?nutrient sensor?, allowing for orchestration of cell growth programs during periods of high nutrient availability and facilitating autophagy during nutrient starvation. We believe this is the most important window yet discovered through which to investigate the basis for the complexity of pathogenic mechanisms in lysosomal diseases. A central goal of the current proposal is therefore to analyze mTOR function across a carefully selected but diverse group of lysosomal diseases and to do so in concert with our earlier and ongoing studies focused on the heterogeneity of lysosomal storage, the dysregulation of autophagy and p62 aggregation, and the unique growth of new, primary dendrites on cortical pyramidal neurons undergoing lysosomal storage of gangliosides. Thus we propose three highly interlinked specific aims: The first to further characterize lysosomal storage heterogeneity as well as p62 aggregation and its relationship to lysosomes; the second to investigate the impact of lysosomal storage on mTORC1 pathway hypo- and hyperactivation and the consequences of each; and the third to determine the association between altered mTOR activation and changes in dendritic complexity, including so-called ?ectopic dendritogenesis?.
|Effective start/end date||9/1/04 → 6/30/22|
- Clinical Neurology
- Molecular Biology
- Cell Biology
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