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Peer-reviewedCC BY 4.0PLOS One

AZP2006 in Parkinson’s disease models: A promising new neuroprotective treatment involving lysosomal homeostasis and the Progranulin/Prosaposin complex

  • Noelle Callizot1
  • Georgia Culley2
  • Grace Flower
  • Laura Rouvière
  • Véronique De Conto
  • Alexandre Wojcinski
  • Catherine Botto
  • Cecilia Estrella
  • Alexandre Henriques
  • Philippe Verwaerde
  1. 1Neuro-Sys, Chemin Départemental, Gardanne, France
  2. 2Alzprotect, Parc Eurasanté, Loos, France
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Abstract

The pathohistological hallmarks of Parkinson’s disease are aggregated alpha-synuclein and other aggregation-prone proteins (Lewy bodies). Recent studies show mechanistic as well as genetic connections between lysosomal dysfunction and Parkinson’s disease pathology. A direct link between lysosomal function and Parkinson’s disease might be the degradation of alpha-synuclein within the lysosomal system. Progranulin is necessary for maintaining lysosomal function, facilitating the activity of several lysosomal enzymes. Progranulin’s exit from the endoplasmic reticulum and its lysosomal availability depend on an interaction with Prosaposin. AZP2006 (INN: Ezeprogind) is a small lysosomotropic neuroprotective molecule currently in clinical development in Progressive Supranuclear Palsy patients. Its neuroprotective effects involve the Progranulin/Prosaposin complex. In this study, we investigated the neuroprotective effects of AZP2006 in several Parkinson’s-like models (vitro and vivo). We showed that AZP2006 was able to counteract a mitochondrial injury as well as the toxicity of alpha-synuclein preformed fibril spreading. We proved that Progranulin was involved in AZP2006’s neuroprotective action, restoring lysosomal homeostasis and ultimately supporting the health of dopaminergic neurons. In light of this evidence, strategies with the aim of improving Progranulin and Prosaposin levels and activity offer a promising therapeutic approach in the context of proteinopathies such as Parkinson’s disease.

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Cite

BibTeXRIS
BibTeX
@article{callizot2026azp2006,
  title = {{AZP2006 in Parkinson’s disease models: A promising new neuroprotective treatment involving lysosomal homeostasis and the Progranulin/Prosaposin complex}},
  author = {Noelle Callizot and Georgia Culley and Grace Flower and Laura Rouvière and Véronique De Conto and Alexandre Wojcinski and Catherine Botto and Cecilia Estrella and Alexandre Henriques and Philippe Verwaerde},
  journal = {PLOS One},
  year = {2026},
  month = sep,
  doi = {10.1371/journal.pone.0359269},
  url = {https://doi.org/10.1371/journal.pone.0359269},
  note = {CC BY 4.0},
}
RIS
TY  - JOUR
TI  - AZP2006 in Parkinson’s disease models: A promising new neuroprotective treatment involving lysosomal homeostasis and the Progranulin/Prosaposin complex
AU  - Noelle Callizot
AU  - Georgia Culley
AU  - Grace Flower
AU  - Laura Rouvière
AU  - Véronique De Conto
AU  - Alexandre Wojcinski
AU  - Catherine Botto
AU  - Cecilia Estrella
AU  - Alexandre Henriques
AU  - Philippe Verwaerde
PY  - 2026
DA  - 2026/09/30
JO  - PLOS One
DO  - 10.1371/journal.pone.0359269
UR  - https://doi.org/10.1371/journal.pone.0359269
AB  - The pathohistological hallmarks of Parkinson’s disease are aggregated alpha-synuclein and other aggregation-prone proteins (Lewy bodies). Recent studies show mechanistic as well as genetic connections between lysosomal dysfunction and Parkinson’s disease pathology. A direct link between lysosomal function and Parkinson’s disease might be the degradation of alpha-synuclein within the lysosomal system. Progranulin is necessary for maintaining lysosomal function, facilitating the activity of several lysosomal enzymes. Progranulin’s exit from the endoplasmic reticulum and its lysosomal availability depend on an interaction with Prosaposin. AZP2006 (INN: Ezeprogind) is a small lysosomotropic neuroprotective molecule currently in clinical development in Progressive Supranuclear Palsy patients. Its neuroprotective effects involve the Progranulin/Prosaposin complex. In this study, we investigated the neuroprotective effects of AZP2006 in several Parkinson’s-like models (vitro and vivo). We showed that AZP2006 was able to counteract a mitochondrial injury as well as the toxicity of alpha-synuclein preformed fibril spreading. We proved that Progranulin was involved in AZP2006’s neuroprotective action, restoring lysosomal homeostasis and ultimately supporting the health of dopaminergic neurons. In light of this evidence, strategies with the aim of improving Progranulin and Prosaposin levels and activity offer a promising therapeutic approach in the context of proteinopathies such as Parkinson’s disease.
SN  - 1932-6203
ER  -