# Cyto-ProSAAS Chaperone Action in Alzheimer's Disease and Frontotemporal Dementia

> **NIH NIH R01** · UNIVERSITY OF MARYLAND BALTIMORE · 2020 · $310,264

## Abstract

SUMMARY
 In our original grant, we proposed to investigate the likely common mechanisms by which the proSAAS
chaperone protects neurons from neurotoxic aggregating proteins and peptides, such as alpha synuclein
and Abeta. We hypothesized that secreted proSAAS sequesters cytotoxic oligomers and fibrils
extracellularly, reducing their concentrations at the synapse, and that endocytosed proSAAS might act
intracellularly to similarly sequester cytotoxic species. Using cultured primary hippocampal and nigral
neurons, we are currently investigating whether secretory proSAAS is involved in intracellular and
extracellular Abeta and alpha synuclein sequestration, and whether secretory proSAAS also accelerates
the intracellular degradation of Abeta and alpha synuclein.
 However, three major findings were made recently in carrying out the above project which take the
work in an unexpected but important new direction. The first is the discovery that delivery of proSAAS to
the cytoplasm, by expression of signal-less proSAAS (“cyto-proSAAS”), results in the liquid-liquid phase
separation and formation of large (2 - 4 µm) symmetric proSAAS spheres, formed by dynamic fusion
of smaller spheres. The second major finding is that these cyto-proSAAS spheres specifically interact
with TDP-43216-414 aggregates, and efficiently sequester these aggregates within the sphere cores.
Thirdly, and most importantly, a collaboration with the Shorter laboratory provided important information
that the interaction between proSAAS and TDP-43 is cytoprotective in a yeast model cell system. The
proposed supplement to our existing “Common Mechanisms” grant is designed to determine whether
cytoplasmic proSAAS should also be studied, not only in proteostatic mechanisms in Alzheimer's disease,
but also in the context of TDP-43 aggregation in another neurodegenerative disease, fronto-temporal
dementia.
 Obtaining a one-year supplement to investigate the functional properties of cyto-proSAAS will provide
us with the opportunity to exploit our exciting findings regarding the highly unusual physical properties of
cyto-proSAAS in forming “aggregate sequestration” spheres. This supplement will also permit us to
determine whether cyto-proSAAS expression is relevant to blocking Abeta and TDP-43 cytotoxicity in
human cells (indeed, cyto-proSAAS expression may represent an improved avenue to achieve our original
specific aim of ameliorating Abeta cytotoxicity -original Proposal Aims 1 and 3). Ultimately, this research
will provide insight into whether proSAAS-mediated cytoplasmic aggregate sequestration should be
further explored as a possible therapeutic approach in neurodegenerative disease. Lastly, it should be
mentioned that given the unpredicted costs of the Covid-19 research shutdown, we clearly require
additional funding to work on cyto-proSAAS, as we will otherwise be solely dedicated to recovering lost
time in completing our original Aims.
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## Key facts

- **NIH application ID:** 10152385
- **Project number:** 3R01AG062222-02S1
- **Recipient organization:** UNIVERSITY OF MARYLAND BALTIMORE
- **Principal Investigator:** IRIS LINDBERG
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $310,264
- **Award type:** 3
- **Project period:** 2019-02-01 → 2023-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10152385

## Citation

> US National Institutes of Health, RePORTER application 10152385, Cyto-ProSAAS Chaperone Action in Alzheimer's Disease and Frontotemporal Dementia (3R01AG062222-02S1). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10152385. Licensed CC0.

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