Benjamin Dehay

Chaperone-mediated autophagy (CMA), regulated by its lysosomal receptor LAMP2A, is a key pathway for αSynuclein (αSyn) clearance and a direct target of αSyn-related neurotoxicity. Rodent studies show that LAMP2A enhancement reverses neurodegeneration, whereas its deficiency accelerates pathology. To test translational relevance, we examined whether increasing LAMP2A expression in nonhuman primates could mitigate α-synucleinopathy induced by injections of Parkinson’s disease patient-derived Lewy body (LB) extract. Increasing LAMP2A expression protected nigral dopaminergic neurons from LB-induced αSyn neurodegeneration, delayed the formation and release of pathology-related αSyn species, and evoked a beneficial effect on motor behavior and on cognitive functions of the primate model. Our findings provide preliminary preclinical evidence supporting CMA enhancement as a therapeutic strategy for αSynucleinopathies.

1. Neurodegenerative diseases (NDs) are a heterogeneous group of disorders characterized by the progressive degeneration of neurons in the central or peripheral nervous system. Under this terminolo...

Proteinopathies are frequently accompanied by co-pathologies, which complicate understanding the pathophysiological mechanisms of neurodegenerative diseases. In this study, we employed a well-characterized baboon cohort to investigate the occurrence of tau pathology following intrastriatal injections of two distinct α-synuclein extracts [small aggregates (SA) and large aggregates (LA)] derived from the brains of patients with Parkinson’s disease (PD). Biochemical and histopathological analyses (6, 12 or 24 months after injections) revealed significantly higher phosphorylated tau expression and greater frequency of neuropil threads in both LA- (n = 18) and SA-injected baboons (n = 12) compared with control animals. We also observed distinct patterns of tau pathology depending on the assembly of α-synuclein aggregates. Baboons injected with SA exhibited tangle-like phosphorylated tau lesions and neuropil threads, with no significant differences across post-injection time points. Moreover, a uniform distribution of tau pathology was detected along the rostro-caudal axis of the medial temporal lobe, affecting neuronal, oligodendroglial and astrocytic cell types. On the other hand, baboons injected with LA exhibited neuropil threads and few glial lesions but lacked phosphorylated tau intraneuronal aggregates. The occurrence of phosphorylated tau lesions was associated with phosphorylated synuclein pathology. These observations suggest a link between nigrostriatal synucleinopathy and limbic tau co-pathology, providing pathophysiological insights into PD dementia.

Neurological diseases remain a leading cause of disability and mortality, in part because systemically administered therapies poorly access diseased brain regions and lack spatiotemporal control. While innovative nanotechnologies offer stable and versatile carriers for drug delivery, they do not inherently enable localized, on-demand release. In parallel, optical neurotechnologies provide precise control of brain activity but cannot deliver bioactive molecules. Here, we bridge these approaches by developing photoactivatable vesicles based on polymeric amphiphiles (polymersomes) that enable light-triggered, spatially confined release of encapsulated compounds in brain tissue. We assessed their safety in primary cell cultures and in vivo. Through the photorelease of CNQX, a competitive AMPA/kainate receptor antagonist, we demonstrated the stability and precise spatiotemporal control of molecular delivery. This work establishes a platform for optically-guided chemical neuromodulation. Beyond applications in basic and preclinical neuroscience, this strategy opens new avenues for targeted therapies in localized brain disorders, including glioblastoma.

ATP13A2 is a lysosomal P5-ATPase highly expressed in the central nervous system, regulating polyamine, metal cation, and calcium homeostasis. Loss-of-function mutations cause an autosomal recessive juvenile form of Parkinson’s disease called Kufor-Rakeb syndrome and other neurodegenerative disorders. Since the first clinical discovery of the Kufor-Rakeb syndrome, numerous ATP13A2-related models have emerged, leading to significant advances in understanding the physiology and pathophysiology of this protein. This review summarizes ATP13A2 structure, function, pathology, and insights gained from cellular and animal models, highlighting their value for elucidating disease mechanisms and therapeutic development across species and experimental systems, relevant to neurodegeneration research broadly.

The extracellular space (ECS) is a complex, dynamic network occupying about 20% of the brain, filled with a cerebrospinal fluid-like solution rich in extracellular matrix (ECM) molecules. ECS properties regulate molecular diffusion, potentially influencing disease-associated protein spread in neurodegenerative diseases. However, its role in tau propagation remains unexplored. Using wild-type mice injected with tau seeds purified from Alzheimer’s disease brain, we applied quantum dot single-particle tracking in live tissue to examine how tau pathology and inflammation influence extracellular diffusion. We observed increased diffusion associated with tau pathology in specific hippocampal regions. Additionally, diffusion profiles differed between cell-dense and cell-sparse areas. Astrocytes showed abnormal internalisation of proteoglycans, and matrix structural components were dysregulated, suggesting a link between altered ECM dynamics and enhanced diffusion. Increased diffusion and altered ECM dynamics might facilitate the spread of tau pathology.

Mutations in the ATP13A2 gene were identified as the cause of Kufor-Rakeb syndrome (KRS), a juvenile-onset form of Parkinson’s disease (PD). Developing relevant and predictive models for the rare PD forms is necessary to understand the pathological mechanisms and validate therapeutic strategies. Herein, we aimed to comprehensively characterize the first transgenic Atp13a2 knockout rat model. Behavioral assessment demonstrated specific developmental deficits in animals with deletion of Atp13a2 . Further analysis revealed that Atp13a2 knockout rats displayed age-dependent fine motor skills deficits and impaired locomotor habituation similar to those observed in PD patients at the early stage of motor symptoms. In contrast, no change in the nigrostriatal integrity was observed. An extended investigation on heavy metals homeostasis, autophagy-related markers, and lipofuscin accumulation showed significant changes reminiscent of KRS. Finally, we tested whether inducing pathology by viral-mediated overexpression of human α-synuclein or human tyrosinase exacerbated the onset or extent of pathological changes. This Atp13a2 KO rat model could help better understand autophagy in PD pathogenesis and open new therapeutic validation opportunities.

Activation of the subventricular zone (SVZ) following cerebral ischemia is one of the brain’s early responses to counteract neuron loss and minimize tissue damage. Impaired brain regions communicate with the SVZ through various chemotactic signals that promote cell migration and differentiation, primarily involving neural stem cells, neuroblasts, or glioblasts. However, the activation of gliogenesis and the role of newly formed astrocytes in the post-ischemic scenario remain subjects of debate. We have previously demonstrated that adenosine release after brain ischemia prompts the SVZ to generate new astrocytes. Here, we used transient brain ischemia in mice to identify the cellular origin of these astrocytes within the SVZ neurogenic niche and investigate their role in the pathological process. By combining immunofluorescence, BrdU-tracing, and genetic cell labeling, we tracked the migration of newborn astrocytes, positive for the proteoglycan marker Thbs4, from the dorsal and medial SVZ to the perilesional barrier surrounding the ischemic core, known as the ‘glial scar’. We found that these Thbs4-positive astrocytes modulate the dense extracellular matrix at the lesion border by both synthesizing and degrading hyaluronan. We also show that while the accumulation of hyaluronan at the lesion site is sufficient to recruit newborn astrocytes, its degradation at the SVZ correlates with gliogenesis. These findings suggest that newborn astrocytes could be a promising pharmacological target for modulating the glial scar after brain ischemia and facilitating tissue regeneration.

The PD-AGE international task force underscores the pivotal role that non-human primate (NHP) models play in advancing our understanding of Parkinson’s disease (PD) and ageing. Due to their close genetic, anatomical, and behavioural similarity to humans, NHPs uniquely enable translational research to bridge basic science towards clinical application. They are indispensable for modelling the complex motor and non-motor symptoms of PD, as well as age-related neurodegeneration. This paper outlines the scientific rationale, methodological strengths, and ethical considerations surrounding NHP use in PD research. We highlight the need for standardised models, innovative tools, and long-term collaborative infrastructure to enhance the translational value of NHP studies. We propose a three-phase roadmap to develop a global research consortium to optimise resource use, improve model fidelity, and accelerate therapeutic development for PD and related neurodegenerative disorders.

The presence of α-synuclein (α-syn) aggregates, such as Lewy bodies in patients with Parkinson’s disease (PD), contributes to dopaminergic cell death. Injection of PD patient–derived α-syn in nonhuman primates has illustrated the exquisite vulnerability of primate dopaminergic neurons. Here, we aimed to elucidate the temporal and spatial pathological changes induced by two distinct α-syn pathogenic structures, having large or small sizes. To unravel the underlying molecular pathways, we conducted a proteomic analysis of the putamen and the entorhinal cortex, two brain regions carrying notable α-syn pathology. We demonstrate that distinct assemblies of α-syn aggregates drive unique pathogenic changes that ultimately result in a comparable extent of nigrostriatal degeneration at the level of nigral dopaminergic neuron cell bodies and striatal dopaminergic terminals. More broadly, our findings identify pathogenic trajectories associated with large or small α-syn aggregates, suggesting the existence of several possible concomitant pathogenic routes in PD.