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

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.

Introduction

Parkinson’s disease (PD) is defined by the progressive, irreversible loss of dopaminergic neurons in the substantia nigra pars compacta (SNpc). Its neuropathological hallmarks include the accumulation of misfolded, aggregated alpha-synuclein (α-syn) and other aggregation-prone proteins (Lewy bodies). Neurodegeneration in PD stems from multiple, interconnected mechanisms, such as proteasomal dysfunction-driven protein aggregation, mitochondrial stress, and impaired dopamine (DA) release. These pathways often converge, amplifying the production of reactive oxygen species (ROS) and oxidative stress, resulting in neuronal death.

Materials and methods

All experiments were carried out in accordance with the National Institutes of Health Guide for the Care and Use of Laboratory Animals and followed current European Union regulations (Directive 2010/63/EU). Animals were housed for acclimation for 1 week in Neuro-Sys facilities and were maintained in a reversed 12 h light/dark cycle. They were placed in ventilated cages and maintained in a room with controlled temperature (21–22 °C), hygrometry (40–60%) and with food and water ad libitum.

Results

Neuroprotective effects of AZP2006 on TH(+) neurons in Dopaminergic-toxin models

Oxidative stress-mediated apoptotic cell death is a major contributing factor to the selective degeneration of an early oxidative stress and activation of caspase 3, leading to apoptotic cell death within the 24 h. In addition, α-syn aggregates accumulate in the cytoplasm of TH(+) neurons after toxin exposure .AZP2006 added concomitantly with 6OHDA was able to prevent neuronal cell death concentration-dependently, with a maximal effect reached at 100 nM. Similarly, AZP2006 fully protected the neurite integrity, as well as protecting synapses (indicated by PSD95 staining).

Conclusion

In this study, AZP2006 (a lysosomotropic compound, see Callizot et al., 2021) protected dopaminergic neurons in both in vitro and in vivo models of PD based on mitotoxin and α-syn PFF-mediated toxicity. AZP2006 reduced α-syn accumulation and alleviated lysosomal stress, while restoring lysosomal function following injury. Furthermore, its mechanism of action in these models was found to involve PGRN, a key regulatory protein of lysosomal activity. These findings reveal that the neuroprotective effects of AZP2006 are mediated through its interaction with a lysosomal-associated target.

Citation: Callizot N, Culley G, Flower G, Rouvière L, De Conto V, Wojcinski A, et al. (2026) AZP2006 in Parkinson’s disease models: A promising new neuroprotective treatment involving lysosomal homeostasis and the Progranulin/Prosaposin complex. PLoS One 21(9): e0359269. https://doi.org/10.1371/journal.pone.0359269

Editor: Miriam A. Hickey, University of Tartu, ESTONIA

Received: August 13, 2025; Accepted: September 11, 2026; Published: September 30, 2026

Copyright: © 2026 Callizot et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Data Availability: All relevant data are within the manuscript and its Supporting Information files.

Funding: This work was funded by Alzprotect (https://www.alzprotect.com/) and Neuro-Sys (https://www.neuro-sys.com/). Alzprotect provided support in the form of salaries for its employees (PV and CE) who are co authors on this study and contracted Neuro Sys, a contract research organization, to perform the experimental work and data analysis. Neuro Sys employed and paid its own staff (NC, GC, GF, LR, VDC, AW, CB and AH), who are also co-authors on this study, and was compensated on a fee for service basis. Philippe Verwaerde (PV), CEO of Alzprotect, received a grant (MJFF-021163) from the Michael J. Fox Foundation (https://www.michaeljfox.org/) for the project entitled “Using AZP2006 (Ezeprogind) to Stabilize Progranulin – A Novel Therapeutic Strategy for GBA1 linked Parkinson’s Disease.” The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Competing interests: This work was funded by Alzprotect. Philippe Verwaerde is the CEO of Alprotect, the company that develops AZP2006.