# Endosomal lysosomal function in neuronal storage disease

> **NIH NIH R01** · ALBERT EINSTEIN COLLEGE OF MEDICINE · 2020 · $504,420

## Abstract

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”.

## Key facts

- **NIH application ID:** 9971351
- **Project number:** 5R01HD045561-17
- **Recipient organization:** ALBERT EINSTEIN COLLEGE OF MEDICINE
- **Principal Investigator:** KOSTANTIN DOBRENIS
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $504,420
- **Award type:** 5
- **Project period:** 2004-09-01 → 2022-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9971351

## Citation

> US National Institutes of Health, RePORTER application 9971351, Endosomal lysosomal function in neuronal storage disease (5R01HD045561-17). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9971351. Licensed CC0.

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