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?.

Public Health Relevance

While individually rare, lysosomal diseases as a whole have an incidence of 1 in 7,000 live births, and are therefore as a group one of the more common types of genetic disease. At least two thirds of these diseases affect brain and typically cause years to decades of intellectual and motor/sensory system decline, with severe consequences for both patients and families. Few treatments are available for lysosomal disorders affecting brain, and almost all are invariably fatal. To better develop therapies we need to know more about pathogenesis ? how defects in what has been considered an inert, end-organelle ultimately causes such serious neurological demise. This proposal provides a new way of thinking about lysosomes and lysosomal diseases and presents a series of testable hypotheses that we believe will provide new insights into the role of the lysosomal system in controlling neuronal metabolism in neurons in both health and disease.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Research Project (R01)
Project #
5R01HD045561-16
Application #
9729021
Study Section
Developmental Brain Disorders Study Section (DBD)
Program Officer
Bardhan, Sujata
Project Start
2004-09-01
Project End
2022-06-30
Budget Start
2019-07-01
Budget End
2020-06-30
Support Year
16
Fiscal Year
2019
Total Cost
Indirect Cost
Name
Albert Einstein College of Medicine
Department
Type
DUNS #
081266487
City
Bronx
State
NY
Country
United States
Zip Code
10461
Kerner-Rossi, Mallory; Gulinello, Maria; Walkley, Steven et al. (2018) Pathobiology of Christianson syndrome: Linking disrupted endosomal-lysosomal function with intellectual disability and sensory impairments. Neurobiol Learn Mem :
Boudewyn, Lauren C; Walkley, Steven U (2018) Current concepts in the neuropathogenesis of mucolipidosis type IV. J Neurochem :
Boudewyn, Lauren C; Sikora, Jakub; Kuchar, Ladislav et al. (2017) N-butyldeoxynojirimycin delays motor deficits, cerebellar microgliosis, and Purkinje cell loss in a mouse model of mucolipidosis type IV. Neurobiol Dis 105:257-270
Yang, Dun-Sheng; Stavrides, Philip; Kumar, Asok et al. (2017) Cyclodextrin has conflicting actions on autophagy flux in vivo in brains of normal and Alzheimer model mice. Hum Mol Genet 26:843-859
Sikora, Jakub; Dworski, Shaalee; Jones, E Ellen et al. (2017) Acid Ceramidase Deficiency in Mice Results in a Broad Range of Central Nervous System Abnormalities. Am J Pathol 187:864-883
Sikora, Jakub; Leddy, Jennifer; Gulinello, Maria et al. (2016) X-linked Christianson syndrome: heterozygous female Slc9a6 knockout mice develop mosaic neuropathological changes and related behavioral abnormalities. Dis Model Mech 9:13-23
Praggastis, Maria; Tortelli, Brett; Zhang, Jessie et al. (2015) A murine Niemann-Pick C1 I1061T knock-in model recapitulates the pathological features of the most prevalent human disease allele. J Neurosci 35:8091-106
Kowalewski, Björn; Heimann, Peter; Ortkras, Theresa et al. (2015) Ataxia is the major neuropathological finding in arylsulfatase G-deficient mice: similarities and dissimilarities to Sanfilippo disease (mucopolysaccharidosis type III). Hum Mol Genet 24:1856-68
Vite, Charles H; Bagel, Jessica H; Swain, Gary P et al. (2015) Intracisternal cyclodextrin prevents cerebellar dysfunction and Purkinje cell death in feline Niemann-Pick type C1 disease. Sci Transl Med 7:276ra26
Yang, Dun-Sheng; Stavrides, Philip; Saito, Mitsuo et al. (2014) Defective macroautophagic turnover of brain lipids in the TgCRND8 Alzheimer mouse model: prevention by correcting lysosomal proteolytic deficits. Brain 137:3300-18

Showing the most recent 10 out of 31 publications