Lysosomes and Î±-synuclein form a dangerous duet leading to neuronal cell death

Bourdenx, Mathieu; Bézard, Erwan; Dehay, Benjamin

doi:10.3389/fnana.2014.00083

Cited by 75 publications

(69 citation statements)

References 101 publications

(128 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…36 However, none of the ALPs-based strategies used so far directly targeted the lysosome, but instead aimed at enhancing the whole autophagy machinery. 37 Here we show that PLGA-aNP are internalized into mammalian cells and trafficked to lysosomes. Furthermore, we reveal the ability of acidic PLGA-aNP to reacidify defective lysosomes to basal level and restore lysosomal deleterious effects caused by PD-linked mutations related to ALPs in 3 different pathological PD models.…”

Section: Discussionmentioning

confidence: 71%

Nanoparticles restore lysosomal acidification defects: Implications for Parkinson and other lysosomal-related diseases

et al. 2016

Self Cite

View full text Add to dashboard Cite

Lysosomal impairment causes lysosomal storage disorders (LSD) and is involved in pathogenesis of neurodegenerative diseases, notably Parkinson disease (PD). Strategies enhancing or restoring lysosomalmediated degradation thus appear as tantalizing disease-modifying therapeutics. Here we demonstrate that poly(DL-lactide-co-glycolide) (PLGA) acidic nanoparticles (aNP) restore impaired lysosomal function in a series of toxin and genetic cellular models of PD, i.e. ATP13A2-mutant or depleted cells or glucocerebrosidase (GBA)-mutant cells, as well as in a genetic model of lysosomal-related myopathy. We show that PLGA-aNP are transported to the lysosome within 24 h, lower lysosomal pH and rescue chloroquine (CQ)-induced toxicity. Re-acidification of defective lysosomes following PLGA-aNP treatment restores lysosomal function in different pathological contexts. Finally, our results show that PLGA-aNP may be detected after intracerebral injection in neurons and attenuate PD-related neurodegeneration in vivo by mechanisms involving a rescue of compromised lysosomes.

show abstract

Section: Discussionmentioning

confidence: 71%

Nanoparticles restore lysosomal acidification defects: Implications for Parkinson and other lysosomal-related diseases

et al. 2016

Self Cite

View full text Add to dashboard Cite

show abstract

“…Lysosomal defects are thought to contribute to de novo aggregation of ␣-syn and impaired autophagic degradation of mature cytosolic aggregates (56,57). Using CHQ to model lysosomal impairment, we measured an increase in the rate of inclusion generation in a seeded aggregation system, suggesting that defects in lysosomal activity and integrity may further accelerate the rate of synucleinopathy transmission.…”

Section: Discussionmentioning

confidence: 98%

Selective imaging of internalized proteopathic α-synuclein seeds in primary neurons reveals mechanistic insight into transmission of synucleinopathies

Karpowicz

Haney

Mihaila

et al. 2017

Journal of Biological Chemistry

137

167

View full text Add to dashboard Cite

Edited by Paul E. FraserDirect cell-to-cell transmission of proteopathic ␣-synuclein (␣-syn) aggregates is thought to underlie the progression of neurodegenerative synucleinopathies. However, the specific intracellular processes governing this transmission remain unclear because currently available model systems are limited. For example, in cell culture models of ␣-syn-seeded aggregation, it is difficult to discern intracellular from extracellular exogenously applied ␣-syn seed species. Herein, we employed fluorescently labeled ␣-syn preformed fibrils (pffs) in conjunction with the membrane-impermeable fluorescence quencher trypan blue to selectively image internalized ␣-syn seeds in cultured primary neurons and to quantitatively characterize the concentration dependence, time course, and inhibition of pff uptake. To study the long-term fates of exogenous ␣-syn pffs in neurons, we developed a pff species labeled at amino acid residue 114 with the environmentally insensitive fluorophore BODIPY or the pH-sensitive dye pHrodo red. We found that pffs are rapidly trafficked along the endolysosomal pathway, where most of the material remains for days. We also found that brief pharmacological perturbation of lysosomes shortly after the pff treatment causes aberrations in intracellular processing of pff seeds concomitant with an increased rate of inclusion formation via recruitment of endogenous ␣-syn to a relatively small number of exogenous seeds. Our results validate a quantitative assay for pff uptake in primary neurons, implicate lysosomal processing as the major fate of internalized proteopathic seeds, and suggest lysosomal integrity as a significant rate-determining step in the transmission of ␣-syn pathology. Further, lysosomal processing of transmitted seeds may represent a new therapeutic target to combat the spread of synucleinopathies.Mounting evidence implicates direct cell-to-cell transmission of misfolded amyloidogenic protein species as a central component underlying the spatiotemporal progression of pathophysiology in numerous proteinopathies (1, 2). In synucleinopathies, including Parkinson's disease, Parkinson's disease with dementia, dementia with Lewy bodies, and multiple system atrophy, the amyloidogenic protein ␣-synuclein (␣-syn) 3 aggregates into Lewy bodies, Lewy neurites, and glial cytoplasmic inclusions (3, 4). These intracellular proteinaceous inclusions have been widely recapitulated in a number of in vivo and cell-based model systems via introduction of pathological, insoluble ␣-syn species from either brain extracts of diseased postmortem tissue or preformed fibrils of recombinant origin (5-10). Despite strong evidence gleaned from these models implicating a causal relationship between exposure of neurons to insoluble ␣-syn aggregates and the subsequent development of inclusions bearing pathological hallmarks of synucleinopathies, the specific processes underlying cell-to-cell transmission of proteopathic seeds and resulting intracellular events leading to the development of pathological ...

show abstract

“…SNCA is expressed throughout the brain, specially in presynaptic nerve terminals, and SNCA-A53T rather tends to form aggregates there are critical to Lewy bodies formation, both familial and idiopathic PD. This aggregation of SNCA is thought to be a key occurence in dopaminergic neuronal cell loss 3,29 . The role of SNCA under normal physiological conditions is not yet completely clear, although there is evidence that implicates SNCA in neurotransmitter release and vesicle turnover at the presynaptic terminals 30 .…”

Section: Discussionmentioning

confidence: 99%

Alpha-synuclein A53T mutation is not frequent on a sample of Brazilian Parkinson’s disease patients

Longo

Pinhel

Gregório

et al. 2015

Arq. Neuro-Psiquiatr.

View full text Add to dashboard Cite

Parkinson's disease (PD) is one of the major degenerative disorders, affecting 2% of the population over 65 years and up to 4% in people over 85 years 1 . In Brazil, statistics show that the incidence of PD amounts to 150/200 cases per 100,000 inhabitants 2 . Most cases of PD are idiopathic 3 . However, in approximately 5%-10% of the cases, there is a genetic component with both dominant and recessive inheritance patterns 3 . The chromosomal loci linked to the familial forms of PD are termed PARK1-13. These loci include six autosomal dominant genes [PARK 1or PARK 4 (alpha synuclein -SNCA), PARK 3 (Lewy bodies), PARK 5 (ubiquitin carboxyl-terminal esterase L1 -UCHL1), PARK 8 (leucine-rich repeat kinase 2 -LRRK2) and PARK13 (HTRA serine peptidase 2 -HTRA2)], 4 recessives genes [PARK 2 ABSTRACT Introduction:The pathogenesis of Parkinson's disease (PD) involves both genetic susceptibility and environmental factors, with focus on the mutation in the alpha-synuclein gene (SNCA). Objective: To analyse the polymorphism SNCA-A53T in patients with familial PD (FPD) and sporadic PD (SPD). Method: A total of 294 individuals were studied, regardless of sex and with mixed ethnicity. The study group with 154 patients with PD, and the control group included 140 individuals without PD. The genotyping of SNCA-A53T was performed by PCR/RFLP. Significance level was p < 0.05. Results: Among all patients, 37 (24%) had FPD and 117 (75.9%) had SPD. The absence of SNCA-A53T mutation was observed in all individuals. Conclusion: SPD is notably observed in patients. However, the SNCA-A53T mutation was absent in all individuals, which does not differ controls from patients. This fact should be confirmed in a Brazilian study case with a more numerous and older population. Keywords:Parkinson's disease, alpha-synuclein, mutation. RESUMO Introdução:A patogênese da doença de Parkinson (DP) envolve fatores ambientais e suscetibilidade genética, destacando-se a mutação de alfa-sinucleína (SNCA.) Objetivos: Analisar a variante genética SNCA-A53T em pacientes com DP familiar (DPF) e DP esporádica (DPE). Método: Foram estudados 294 indivíduos, independente de sexo, com etnia miscigenada, sendo 154 com DP e 140 sem a doença (grupo controle). A genotipagem de SNCA-A53T foi realizada por PCR/RFLP. Nível de significância para p < 0,05. Resultados: Entre os pacientes, 37(24%) tinham DPF e 117 (75,9%) DPE. A ausência da mutação SNCA-A53T em todos os indivíduos. Conclusão: DPE é destacada entre os pacientes, no entanto a mutação SNCA-A53T ausente em todos os indivíduos, não diferenciando os grupo controle e pacientes, o que deve ser confirmado em população brasileira, considerando uma ampla casuística, além da ancestralidade.Palavras-chave: doença de Parkinson, alfa sinucleína, mutação.

show abstract

Lysosomes and Î±-synuclein form a dangerous duet leading to neuronal cell death

Cited by 75 publications

References 101 publications

Nanoparticles restore lysosomal acidification defects: Implications for Parkinson and other lysosomal-related diseases

Nanoparticles restore lysosomal acidification defects: Implications for Parkinson and other lysosomal-related diseases

Selective imaging of internalized proteopathic α-synuclein seeds in primary neurons reveals mechanistic insight into transmission of synucleinopathies

Alpha-synuclein A53T mutation is not frequent on a sample of Brazilian Parkinson’s disease patients

Contact Info

Product

Resources

About