# Activation of Neuronal Degradative Pathways to Ameliorate Prion Disease

> **NIH NIH R56** · SCRIPPS RESEARCH INSTITUTE, THE · 2023 · $871,963

## Abstract

ABSTRACT
Prionopathies are rare human neurodegenerative diseases characterized by spongiform change, gliosis, and by
the deposition of misfolded prion protein (PrP) aggregates inside and outside of neurons across the brain. While
cellular mechanisms remain largely undefined, evidence points toward a particular vulnerability of axons to the
formation of misfolded protein aggregates, and their accumulation inside lysosome-like compartments suggests
defective lysosomal degradative pathways in axons. Indeed, axonal dystrophies with enlarged endosomes occur
early in disease in virtually all neurodegenerative diseases including Alzheimer’s Disease and Alzheimer’s
Disease related dementias, where lysosomal dysfunction is well-recognized. Compelling evidence shows that
PrP aggregates impair neuronal function by driving the accumulation of organelles/vesicles and cytoskeletal
elements, thus poisoning axonal transport. This application builds on our previous findings that identified an
endolysosomal pathway unique to axons, that promotes the initial stages of formation of misfolded mutant PrP
aggregates inside enlarged endolysosome structures that do not acidify and thus fail to degrade misfolded and
aggregated mutant PrP from axons, indicating impaired lysosomal degradation. We showed that in this axonal
rapid endosomal sorting and transport-dependent aggregation (ARESTA) pathway, the molecular motor kinesin-
1C (KIF5C) transports vesicles carrying pathogenic and misfolded mutant PrP into axons resulting in neurotoxic
axonal dystrophies filled with PrP aggregates inside endosomes that we term ‘endoggresomes’. Reducing the
function of ARESTA genes, including kinesin-1, efficiently inhibits mutant PrP endoggresome formation and
restores neuronal function. Furthermore, we have identified and tested a lysosomal flux activator (LFA) small
molecule that efficiently inhibits and/or clears mutant PrP aggregate-containing endoggresomes from axons,
restoring neuronal function. These findings form the premise of the central hypothesis of this grant that states
that targeting neurotoxic axonal aggregates by genetic inhibition of ARESTA or by pharmacologic activation of
lysosomal flux, prevents the formation of misfolded PrP aggregates and/or clears them, and ameliorates disease
phenotypes in cellular and mouse models of prion disease. Our main LFA candidate molecule degrades PrP
aggregates in the lower nanomolar range, does not show any overt signs of toxicity in mice, and has brain
penetrance. The proposed aims will test the efficacy of LFAs in cellular (neuronal) and mouse models of familial
and infectious prion disease. We will also identify the mechanisms of action (MoA) of LFAs. Our findings reveal
a therapeutic strategy to treat prionopathies by genetic and pharmacological activation of macroautophagy. As
lysosomal clearance is a common pathway impaired in Alzheimer’s Disease and Alzheimer’s Disease related
dementias, our findings are expected to also be releva...

## Key facts

- **NIH application ID:** 10855708
- **Project number:** 1R56NS131648-01
- **Recipient organization:** SCRIPPS RESEARCH INSTITUTE, THE
- **Principal Investigator:** SANDRA E Encalada
- **Activity code:** R56 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2023
- **Award amount:** $871,963
- **Award type:** 1
- **Project period:** 2023-07-01 → 2025-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10855708

## Citation

> US National Institutes of Health, RePORTER application 10855708, Activation of Neuronal Degradative Pathways to Ameliorate Prion Disease (1R56NS131648-01). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10855708. Licensed CC0.

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