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Lysosomal impairment is strongly implicated in Parkinson's disease (PD). Among the several PD-linked genes, the ATP13A2 gene, associated with the PARK9 locus, encodes a transmembrane lysosomal P5-type ATPase. Mutations in the ATP13A2 gene were primarily identified as the cause of Kufor-Rakeb syndrome (KRS), a juvenile-onset form of PD. Subsequently, an increasing list of several mutations has been described. These mutations result in truncation of the ATP13A2 protein, leading to a loss of function but surprisingly causing heterogeneity and variability in the clinical symptoms associated with different brain pathologies. In vitro studies show that its loss compromises lysosomal function, contributing to cell death. To understand the role of ATP13A2 dysfunction in disease, we disrupted its expression through a viral vector-based approach in nonhuman primates. Here, in this pilot study, we injected bilaterally into the substantia nigra of macaques, a lentiviral vector expressing an ATP13A2 small hairpin RNA. Animals were terminated five months later, and brains were harvested and compared with historical non-injected control brains to evaluate cerebral pathological markers known to be affected in KRS and PD. We characterised the pattern of dopaminergic loss in the striatum and the substantia nigra, the regional distribution of α-synuclein immunoreactivity in several brain structures, and its pathological status (i.e., S129 phosphorylation), the accumulation of heavy metals in nigral sections and occurrence of lysosomal dysfunction. This proof-of-concept experiment highlights the potential value of lentivirus-mediated ATP13A2 silencing to induce significant and ongoing degeneration in the nigrostriatal pathway, α-synuclein pathology, and iron accumulation in nonhuman primates.
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Decades of research have identified the pathological and pathophysiological hallmarks of Parkinson's disease (PD): profound deficit in brain dopamine and other monoamines, pathological α-synuclein aggregation, synaptic and neuronal network dysfunction, aberrant proteostasis, altered energy homeostasis, inï¬ammation, and neuronal cell death. The purpose of this contribution is to present the phenocopy aspect, pathogenic, and etiologic nonhuman primate (NHP) models of PD to readers with limited prior knowledge of PD so that they are ready to start working on PD. How NHPs, the closest species to man on which we can model diseases, contribute to the knowledge progress and how these models represent an invaluable translational step in therapeutic development are highlighted.
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INTRODUCTION: The "prion-like" features of Alzheimer's disease (AD) tauopathy and its relationship with amyloid-ß (Aß) have never been experimentally studied in primates phylogenetically close to humans. METHODS: We injected 17 macaques in the entorhinal cortex with nanograms of seeding-competent tau aggregates purified from AD brains or control extracts from aged-matched healthy brains, with or without intracerebroventricular co-injections of oligomeric-Aß. RESULTS: Pathological tau injection increased cerebrospinal fluid (CSF) p-tau181 concentration after 18 months. Tau pathology spreads from the entorhinal cortex to the hippocampal trisynaptic loop and the cingulate cortex, resuming the experimental progression of Braak stage I to IV. Many AD-related molecular networks were impacted by tau seeds injections regardless of Aß injections in proteomic analyses. However, we found mature neurofibrillary tangles, increased CSF total-tau concentration, and pre- and postsynaptic degeneration only in Aß co-injected macaques. DISCUSSION: Oligomeric-Aß mediates the maturation of tau pathology and its neuronal toxicity in macaques but not its initial spreading. HIGHLIGHTS: This study supports the "prion-like" properties of misfolded tau extracted from AD brains. This study empirically validates the Braak staging in an anthropomorphic brain. This study highlights the role of oligomeric Aß in driving the maturation and toxicity of tau pathology. This work establishes a novel animal model of early sporadic AD that is closer to the human pathology.
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Doença de Alzheimer , Príons , Animais , Humanos , Idoso , Doença de Alzheimer/patologia , Macaca/metabolismo , Proteômica , Proteínas tau/metabolismo , Peptídeos beta-Amiloides/metabolismo , Encéfalo/patologiaRESUMO
Aggregation of α-synuclein (α-syn) is the cornerstone of neurodegenerative diseases termed synucleinopathies, which include Parkinson's Disease (PD), Dementia with Lewy Bodies (DLB), and Multiple System Atrophy (MSA). These synucleinopathies are characterized by the deposit of aggregated α-syn in intracellular inclusions observable in neurons and glial cells. In PD and DLB, these aggregates, predominantly located in neurons, are called Lewy Bodies (LBs). These LBs are one of the pathological hallmarks of PD and DLB, alongside dopaminergic neuron loss in the substantia nigra. Previous studies have demonstrated the ability of PD patient-derived LB fractions to induce nigrostriatal neurodegeneration and α-syn pathology when injected into the striatum or the enteric nervous system of non-human primates. Here, we report the pathological consequences of injecting these LB fractions into the cortex of non-human primates. To this end, we inoculated mesencephalic PD patient-derived LB fractions into the prefrontal cortex of baboon monkeys terminated one year later. Extensive analyses were performed to evaluate pathological markers known to be affected in LB pathologies. We first assessed the hypothesized presence of phosphorylated α-syn at S129 (pSyn) in the prefrontal cortices. Second, we quantified the neuronal, microglial, and astrocytic cell survival in the same cortices. Third, we characterized these cortical LB injections' putative impact on the integrity of the nigrostriatal system. Overall, we observed pSyn accumulation around the injection site in the dorsal prefrontal cortex, in connected cortical regions, and further towards the striatum, suggesting α-syn pathological propagation. The pathology was also accompanied by neuronal loss in these prefrontal cortical regions and the caudate nucleus, without, however, loss of nigral dopamine neurons. In conclusion, this pilot study provides novel data demonstrating the toxicity of patient-derived extracts, their potential to propagate from the cortex to the striatum in non-human primates, and a possible primate model of DLB.
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The role of alpha-synuclein in Parkinson's disease has been heavily investigated since its discovery as a component of Lewy bodies. Recent rodent data demonstrate that alpha-synuclein strain structure is critical for differential propagation and toxicity. Based on these findings, we have compared, for the first time, in this pilot study, the capacity of two alpha-synuclein strains and patient-derived Lewy body extracts to model synucleinopathies after intra-putaminal injection in the non-human primate brain. Functional alterations triggered by these injections were evaluated in vivo using glucose positron emission tomography imaging. Post-mortem immunohistochemical and biochemical analyses were used to detect neuropathological alterations in the dopaminergic system and alpha-synuclein pathology propagation. In vivo results revealed a decrease in glucose metabolism more pronounced in alpha-synuclein strain-injected animals. Histology showed a decreased number of dopaminergic tyrosine hydroxylase-positive cells in the substantia nigra to different extents according to the inoculum used. Biochemistry revealed that alpha-synuclein-induced aggregation, phosphorylation, and propagation in different brain regions are strain-specific. Our findings show that distinct alpha-synuclein strains can induce specific patterns of synucleinopathy in the non-human primate, changes in the nigrostriatal pathway, and functional alterations that resemble early-stage Parkinson's disease.
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Doença de Parkinson , Sinucleinopatias , Animais , alfa-Sinucleína/metabolismo , Doença de Parkinson/metabolismo , Projetos Piloto , Corpos de Lewy/metabolismo , Sinucleinopatias/patologia , Substância Negra/metabolismo , Dopamina/metabolismo , Primatas/metabolismoRESUMO
The multimerization of active compounds has emerged as a successful approach, mainly to address the multivalency of numerous biological targets. Regarding the pharmaceutical prospect, carrying several active ingredient units on the same synthetic scaffold was a practical approach to enhance drug delivery or biological activity with a lower global concentration. Various examples have highlighted better in vivo stability and therapeutic efficiency through sustained action over monomeric molecules. The synthesis strategy aims to covalently connect biologically active monomers to a central core using simple and efficient reaction steps. Despite extensive studies reporting carbohydrate or even peptide multimerization developed for therapeutic activities, very few are concerned with nucleic acid derivatives. In the context of our efforts to build non-viral nucleolipid (NL)-based nanocarriers to restore lysosomal acidification defects, we report here a straightforward synthesis of tetrameric NLs, designed as prodrugs that are able to release no more than one but four biocompatible succinic acid units. The use of oil-in-water nanoemulsion-type vehicles allowed the development of lipid nanosystems crossing the membranes of human neuroblastoma cells. Biological evaluations have proved the effective release of the acid within the lysosome of a genetic and cellular model of Parkinson's disease through the recovery of an optimal lysosomal pH associated with a remarkably fourfold lower concentration of active ingredients than with the corresponding monomers. Overall, these results suggest the feasibility, the therapeutic opportunity, and the better tolerance of multimeric compounds compared to only monomer molecules.
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Pró-Fármacos , Ácido Succínico , Humanos , Sistemas de Liberação de Medicamentos , Lisossomos , Concentração de Íons de HidrogênioRESUMO
The progressive aging of the population and the fact that Parkinson's disease currently does not have any curative treatment turn out to be essential issues in the following years, where research has to play a critical role in developing therapy. Understanding this neurodegenerative disorder keeps advancing, proving the discovery of new pathogenesis-related genes through genome-wide association analysis. Furthermore, the understanding of its close link with the disruption of autophagy mechanisms in the last few years permits the elaboration of new animal models mimicking, through multiple pathways, different aspects of autophagic dysregulation, with the presence of pathological hallmarks, in brain regions affected by Parkinson's disease. The synergic advances in these fields permit the elaboration of multiple therapeutic strategies for restoring autophagy activity. This review discusses the features of Parkinson's disease, the autophagy mechanisms and their involvement in pathogenesis, and the current methods to correct this cellular pathway, from the development of animal models to the potentially curative treatments in the preclinical and clinical phase studies, which are the hope for patients who do not currently have any curative treatment.
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Doença de Parkinson , Animais , Doença de Parkinson/metabolismo , Estudo de Associação Genômica Ampla , Autofagia/genética , Encéfalo/metabolismoRESUMO
Progressive supranuclear palsy is a primary tauopathy affecting both neurons and glia and is responsible for both motor and cognitive symptoms. Recently, it has been suggested that progressive supranuclear palsy tauopathy may spread in the brain from cell to cell in a 'prion-like' manner. However, direct experimental evidence of this phenomenon, and its consequences on brain functions, is still lacking in primates. In this study, we first derived sarkosyl-insoluble tau fractions from post-mortem brains of patients with progressive supranuclear palsy. We also isolated the same fraction from age-matched control brains. Compared to control extracts, the in vitro characterization of progressive supranuclear palsy-tau fractions demonstrated a high seeding activity in P301S-tau expressing cells, displaying after incubation abnormally phosphorylated (AT8- and AT100-positivity), misfolded, filamentous (pentameric formyl thiophene acetic acid positive) and sarkosyl-insoluble tau. We bilaterally injected two male rhesus macaques in the supranigral area with this fraction of progressive supranuclear palsy-tau proteopathic seeds, and two other macaques with the control fraction. The quantitative analysis of kinematic features revealed that progressive supranuclear palsy-tau injected macaques exhibited symptoms suggestive of parkinsonism as early as 6 months after injection, remaining present until euthanasia at 18 months. An object retrieval task showed the progressive appearance of a significant dysexecutive syndrome in progressive supranuclear palsy-tau injected macaques compared to controls. We found AT8-positive staining and 4R-tau inclusions only in progressive supranuclear palsy-tau injected macaques. Characteristic pathological hallmarks of progressive supranuclear palsy, including globose and neurofibrillary tangles, tufted astrocytes and coiled bodies, were found close to the injection sites but also in connected brain regions that are known to be affected in progressive supranuclear palsy (striatum, pallidum, thalamus). Interestingly, while glial AT8-positive lesions were the most frequent near the injection site, we found mainly neuronal inclusions in the remote brain area, consistent with a neuronal transsynaptic spreading of the disease. Our results demonstrate that progressive supranuclear palsy patient-derived tau aggregates can induce motor and behavioural impairments in non-human primates related to the prion-like seeding and spreading of typical pathological progressive supranuclear palsy lesions. This pilot study paves the way for supporting progressive supranuclear palsy-tau injected macaque as a relevant animal model to accelerate drug development targeting this rare and fatal neurodegenerative disease.
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Doenças Neurodegenerativas , Paralisia Supranuclear Progressiva , Tauopatias , Animais , Masculino , Paralisia Supranuclear Progressiva/patologia , Proteínas tau/metabolismo , Doenças Neurodegenerativas/patologia , Macaca mulatta/metabolismo , Projetos Piloto , Tauopatias/patologia , Encéfalo/patologiaRESUMO
Parkinson's disease (PD) is pathologically characterized by intracellular α-synuclein-rich protein aggregates, named Lewy bodies (LB), and by the progressive loss of dopaminergic neurons in the substantia nigra. Several heavy metals, including zinc (Zn), have been suggested to play a role in PD progression, although the exact role of Zn in neurodegeneration remains to be fully elucidated. To address this gap, we investigated the effects of Zn modulation on the progression of degeneration in mice injected with PD patient-derived LB-extracts carrying toxic α-synuclein aggregates. Zn modulation was achieved using either a clioquinol-enriched diet, a Zn ionophore that redistributes cellular Zn, or a Zn-enriched diet that increases Zn levels. Clioquinol treatment significantly prevented dopaminergic neurodegeneration and reduced α-synuclein-associated pathology in LB-injected mice, while no differences were observed with Zn supplementation. Biochemical analyses further demonstrate that the expression levels of vesicle-specific Zn transporter ZnT3 in the striatum of LB-injected mice treated with clioquinol were decreased, suggesting an intracellular redistribution of Zn. Additionally, we found that clioquinol modulates the autophagy-lysosomal pathway by enhancing lysosomal redistribution within the neuronal compartments. Collectively, we found that in vivo pharmacological chelation of Zn, by dampening Zn-mediated cytotoxicity, can result in an overall attenuation of PD-linked lysosomal alterations and dopaminergic neurodegeneration. The results support zinc chelation as a disease-modifying strategy for treating PD.
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Clioquinol , Doença de Parkinson , Animais , Encéfalo/metabolismo , Clioquinol/farmacologia , Clioquinol/uso terapêutico , Dopamina/metabolismo , Neurônios Dopaminérgicos/metabolismo , Humanos , Ionóforos/farmacologia , Ionóforos/uso terapêutico , Camundongos , Doença de Parkinson/patologia , Substância Negra/patologia , Extratos de Tecidos , Zinco/metabolismo , alfa-Sinucleína/metabolismoRESUMO
The Autophagy Lysosomal Pathway is one of the most important mechanisms for removing dysfunctional cellular components. Increasing evidence suggests that alterations in this pathway play a pathogenic role in Parkinson's disease, making it a point of particular vulnerability. Numerous studies have proposed nanotechnologies as a promising approach for delivering active substances within the central nervous system to treat and diagnose neurodegenerative diseases. In this context, the aim was to propose the development of a new pharmaceutical technology for the treatment of neurodegenerative diseases. We designed a trehalose-based nanosystem by combining both a small natural autophagy enhancer molecule named trehalose and an amphiphilic nucleolipid conjugate. To improve nucleolipid protection and cellular uptake, these conjugates were formulated by rapid mixing in either solid lipid nanoparticles (Ø = 120.4 ± 1.4 nm) or incorporated into poly(lactic-co-glycolic acid) nanoparticles (Ø = 167.2 ± 2.4 nm). In vitro biological assays demonstrated a safe and an efficient cellular uptake associated with autophagy induction. Overall, these nucleolipid-based formulations represent a promising new pharmaceutical tool to deliver trehalose and restore the autophagy impaired function.
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Parkinson's disease (PD) is an age-related neurodegenerative disorder characterized by the loss of dopaminergic neurons in the substantia nigra, associated with the accumulation of misfolded α-synuclein and lysosomal impairment, two events deemed interconnected. Protein aggregation is linked to defects in degradation systems such as the autophagy-lysosomal pathway, while lysosomal dysfunction is partly related to compromised acidification. We have recently proven that acidic nanoparticles (aNPs) can re-acidify lysosomes and ameliorate neurotoxin-mediated dopaminergic neurodegeneration in mice. However, no lysosome-targeted approach has yet been tested in synucleinopathy models in vivo. Here, we show that aNPs increase α-synuclein degradation through enhancing lysosomal activity in vitro. We further demonstrate in vivo that aNPs protect nigral dopaminergic neurons from cell death, ameliorate α-synuclein pathology, and restore lysosomal function in mice injected with PD patient-derived Lewy body extracts carrying toxic α-synuclein aggregates. Our results support lysosomal re-acidification as a disease-modifying strategy for the treatment of PD and other age-related proteinopathies.
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Nanopartículas , Doença de Parkinson , Animais , Humanos , Lisossomos/metabolismo , Camundongos , Doença de Parkinson/metabolismo , Substância Negra/metabolismo , alfa-Sinucleína/metabolismoRESUMO
Synucleinopathies encompass several neurodegenerative diseases, which include Parkinson's disease, dementia with Lewy bodies and multiple system atrophy. These diseases are characterized by the deposit of α-synuclein aggregates in intracellular inclusions in neurons and glial cells. Unlike Parkinson's disease and dementia with Lewy bodies, where aggregates are predominantly neuronal, multiple system atrophy is associated with α-synuclein cytoplasmic inclusions in oligodendrocytes. Glial cytoplasmic inclusions are the pathological hallmark of multiple system atrophy and are associated with neuroinflammation, modest demyelination and, ultimately, neurodegeneration. To evaluate the possible pathogenic role of glial cytoplasmic inclusions, we inoculated glial cytoplasmic inclusion-containing brain fractions obtained from multiple system atrophy patients into the striatum of non-human primates. After a 2-year in vivo phase, extensive histochemical and biochemical analyses were performed on the whole brain. We found loss of both nigral dopamine neurons and striatal medium spiny neurons, as well as loss of oligodendrocytes in the same regions, which are characteristics of multiple system atrophy. Furthermore, demyelination, neuroinflammation and α-synuclein pathology were also observed. These results show that the α-synuclein species in multiple system atrophy-derived glial cytoplasmic inclusions can induce a pathological process in non-human primates, including nigrostriatal and striatofugal neurodegeneration, oligodendroglial cell loss, synucleinopathy and gliosis. The present data pave the way for using this experimental model for MSA research and therapeutic development.
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Doenças Desmielinizantes , Doença por Corpos de Lewy , Atrofia de Múltiplos Sistemas , Doença de Parkinson , Sinucleinopatias , Animais , Encéfalo/patologia , Doenças Desmielinizantes/patologia , Humanos , Corpos de Inclusão/metabolismo , Doença por Corpos de Lewy/patologia , Atrofia de Múltiplos Sistemas/patologia , Doença de Parkinson/patologia , alfa-Sinucleína/metabolismoRESUMO
The vast majority of neurodegenerative diseases are associated with an accumulation of undegraded and aggregated proteins. Hence the word proteinopathies is now used to refer to these neurodegenerative diseases. The synucleinopathies are one component of them, in particular in Parkinson's disease. The neuropathological features of Parkinson's disease are the progressive loss of dopamine neurons in the midbrain and the formation of aggregates composed mainly of a-synuclein protein. Experimental evidence suggests that under pathological conditions, normal soluble a-synuclein protein adopts an abnormal folding and subsequently aggregates, with a propensity to spread throughout the central nervous system. This review article discusses the specifics of a-synuclein aggregation and emerging mechanisms for understanding its spread and aims at providing a molecular explanation for the progression of the disease in humans.
TITLE: Maladie de Parkinson - Le rôle de la synucléine. ABSTRACT: La vaste majorité des maladies neurodégénératives sont associées à une accumulation de protéines non dégradées et agrégées. On appelle ainsi ces maladies, protéinopathies. Les synucléinopathies en sont une des composantes, en particulier la maladie de Parkinson. Les caractéristiques neuropathologiques de la maladie de Parkinson comprennent la perte progressive de neurones dopaminergiques du mésencéphale et la formation d'agrégats protéiques, constitués notamment de la protéine a-synucléine. Des preuves expérimentales suggèrent que dans des conditions pathologiques, cette protéine, normalement soluble, adopte un repliement anormal et s'agrège, avec une propension à se propager dans tout le système nerveux central. Dans cette Synthèse, nous discuterons des spécificités de l'agrégation de l'a-synucléine et de ses mécanismes, qui permettent désormais de comprendre sa propagation et fournissent une explication moléculaire à la progression de la maladie chez l'homme.
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Doenças Neurodegenerativas , Doença de Parkinson , Neurônios Dopaminérgicos , Humanos , alfa-SinucleínaRESUMO
For the last two decades, pathogenic concepts in Parkinson disease (PD) have revolved around the toxicity and spread of α-synuclein. Thus, α-synuclein would follow caudo-rostral propagation from the periphery to the central nervous system, first producing non-motor manifestations (such as constipation, sleep disorders and hyposmia), and subsequently impinging upon the mesencephalon to account for the cardinal motor features before reaching the neocortex as the disease evolves towards dementia. This model is the prevailing theory of the principal neurobiological mechanism of disease. Here, we scrutinize the temporal evolution of motor and non-motor manifestations in PD and suggest that, even though the postulated bottom-up mechanisms are likely to be involved, early involvement of the nigrostriatal system is a key and prominent pathophysiological mechanism. Upcoming studies of detailed clinical manifestations with newer neuroimaging techniques will allow us to more closely define, in vivo, the role of α-synuclein aggregates with respect to neuronal loss during the onset and progression of PD.
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Vias Eferentes/fisiopatologia , Vias Neurais/fisiopatologia , Doença de Parkinson/fisiopatologia , Animais , Humanos , Doença de Parkinson/genética , alfa-Sinucleína/genética , alfa-Sinucleína/fisiologiaRESUMO
Adeno-associated virus (AAV) vectors are increasingly used as an effective and safe approach to deliver genetic material to the central nervous system (CNS). The AAV9-derived variants, AAV-PHP. B and AAV-PHP.eB, reportedly broadly transduce cells throughout the CNS compared to the original serotype 9, AAV9. As non-human primate data are scarce, we here evaluated the CNS transduction efficiencies after lumbar intrathecal bolus delivery of identical doses of either AAV-PHP. B:CAG-EGFP or AAV-PHP. eB:CAG-EGFP in rhesus macaque monkeys. AAV-PHP.eB achieved a more efficient and widespread CNS transduction compared to AAV-PHP.B. We report a strong neuronal and oligodendroglial tropism for both variants in the putamen and in the hippocampus. This proof-of-concept experiment highlights the potential value of intrathecal infusions of AAV-PHP.eB to distribute genetic material in the CNS with cell-type specificity and introduces a new opportunity to model brain diseases in rhesus macaque monkeys and further develop gene therapies targeting the CNS in humans.
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Increasing evidence suggests that lysosomal dysfunction has a pathogenic role in neurodegenerative diseases. In particular, an increase in lysosomal pH has been reported in different cellular models of Parkinson's disease. Thus, targeting lysosomes has emerged as a promising approach. More specifically, regulating its pH could play a central role against the neurodegeneration process. To date, only a few agents specifically targeting lysosomal pH are reported in the literature, partly due to the challenge of crossing the Blood-Brain-Barrier (BBB), preventing drug penetration into the central nervous system (CNS). To develop chronic treatments for neurodegenerative diseases, crossing the BBB is crucial. We report herein the conception and synthesis of an innovative DNA derivative-based nanocarrier. Nucleolipids, carrying a biocompatible organic acid as an active ingredient, were designed and synthesized as prodrugs. They were successfully incorporated into an oil-in-water nanoemulsion vehicle to cross biological membranes and then release effectively biocompatible acidic components to restore the functional lysosomal pH of neuronal cells. Biological assays on a genetic cell model of Parkinson's disease highlighted the non-toxicity of such nucleolipids after cellular uptake and their ability (at c = 40 µM) to fully restore lysosomal acidity.
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The neuropathological changes of limbic-predominant age-related TDP-43 encephalopathy (LATE) are frequent in the aged population and are now recognized as a cause of memory impairment. However, it remains unknown if this proteinopathy is also present in other primate species. We thus investigated the presence and distribution of TDP-43 pathology in the hippocampus and amygdala of 7 aged memory-impaired rhesus macaques (Macaca mulatta, 18-32 years old) from 2 different cohorts. While present in an FTLD-TDP case used as a positive control for immunostaining, we found no TDP-43 or phosphorylated TDP-43 immunoreactive neuronal cytoplasmic inclusion in the amygdala or the hippocampus of these aged animals (as well as in young and mature macaques used as negative controls). We concluded that LATE is probably a human-specific condition, such as many other proteinopathies, and does not participate in age-related memory impairment in non-human primates.
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Envelhecimento/patologia , Envelhecimento/psicologia , Encefalopatias/patologia , Sistema Límbico/patologia , Transtornos da Memória/patologia , Proteinopatias TDP-43/patologia , Envelhecimento/metabolismo , Animais , Encefalopatias/complicações , Proteínas de Ligação a DNA/metabolismo , Sistema Límbico/metabolismo , Macaca mulatta , Transtornos da Memória/etiologia , Resultados Negativos , Proteinopatias TDP-43/complicaçõesRESUMO
Treatment of neurodegenerative diseases has become one of the most challenging topics of the last decades due to their prevalence and increasing societal cost. The crucial point of the non-invasive therapeutic strategy for neurological disorder treatment relies on the drugs' passage through the blood-brain barrier (BBB). Indeed, this biological barrier is involved in cerebral vascular homeostasis by its tight junctions, for example. One way to overcome this limit and deliver neuroprotective substances in the brain relies on nanotechnology-based approaches. Poly(lactic-co-glycolic acid) nanoparticles (PLGA NPs) are biocompatible, non-toxic, and provide many benefits, including improved drug solubility, protection against enzymatic digestion, increased targeting efficiency, and enhanced cellular internalization. This review will present an overview of the latest findings and advances in the PLGA NP-based approach for neuroprotective drug delivery in the case of neurodegenerative disease treatment (i.e., Alzheimer's, Parkinson's, Huntington's diseases, Amyotrophic Lateral, and Multiple Sclerosis).
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Synucleinopathies are neurodegenerative diseases characterized by the presence of α-synuclein-positive intracytoplasmic inclusions in the central nervous system. Multiple experimental models have been extensively used to understand better the mechanisms involved in the pathogenesis of synucleinopathy. Non-human primate (NHP) models are of interest in neurodegenerative diseases as they constitute the highest relevant preclinical model in translational research. They also contribute to bringing new insights into synucleinopathy's pathogenicity and help in the quest and validation of therapeutical strategies. Here, we reviewed the different NHP models that have recapitulated key characteristics of synucleinopathy, and we aimed to highlight the contribution of NHP in mechanistic and translational approaches for synucleinopathies.