α-Synuclein Overexpression Induces Lysosomal Dysfunction and Autophagy Impairment in Human Neuroblastoma SH-SY5Y

Nascimento, Ana Carolina; Erustes, Adolfo Garcia; Reckziegel, Patrícia; Bincoletto, Cláudia; Ureshino, Rodrigo Portes; Pereira, Gustavo José da Silva

doi:10.1007/s11064-020-03126-8

Cited by 31 publications

(22 citation statements)

References 67 publications

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“…To determine whether wild‐type α‐syn overexpression may impact the intraluminal pH of lysosomes, we measured lysosomal pH with LysoSensor Yellow/Blue DND‐160. We observed that lysosomal pH acidification is compromised specifically in M17‐WTsyn (Figure 1d) in agreement with a recent study (Nascimento et al, 2020). Also, in vitro assays analyzing the activity of two lysosomal enzymes (i.e., ACP2 [acid phosphatase 2] and HEX/β‐hexosaminidase) in lysosomal fractions of M17‐WTsyn cells confirmed a markedly reduced proteolytic activity of these enzymes relative to control cells (Figure 1e,f).…”

Section: Resultssupporting

confidence: 93%

“…While α‐syn can be cleared by UPS, the main pathway for its degradation appears to be mediated by the lysosome (Webb et al, 2003). Because α‐syn can be degraded by both macroautophagy (Vogiatzi et al, 2008) and chaperone‐mediated autophagy (CMA) (Cuervo et al, 2004), we next explored whether aNPs could impact ALP, a system burdened by increased α‐syn load (Arotcarena et al, 2019; Martinez‐Vicente et al, 2008; Nascimento et al, 2020; Tang et al, 2021). To assess the impact of lysosomal re‐acidification by aNPs, we examined the autophagy flux in cells overexpressing α‐syn.…”

Section: Resultsmentioning

confidence: 99%

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Acidic nanoparticles protect against α‐synuclein‐induced neurodegeneration through the restoration of lysosomal function

et al. 2022

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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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Section: Resultssupporting

confidence: 93%

Section: Resultsmentioning

confidence: 99%

Acidic nanoparticles protect against α‐synuclein‐induced neurodegeneration through the restoration of lysosomal function

et al. 2022

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“…These aggregates, which could be degraded by the ALP 31 , 32 , may in turn impair mitochondrial, autophagic, and lysosomal functions, aggravating the toxic protein aggregates 33 . α -Syn overexpression was found to generate ER stress, along with lysosomal pH alkalization, lower LAMP1 levels, and a disruption of lysosomal morphology and distribution, impairing autophagy 34 . Via abolishing the hydrolase trafficking, the accumulation of α -syn dampens the ability of lysosomes to degrade dopamine in human midbrain dopamine models 35 .…”

Section: Molecular Mechanisms Of Autolysosome Pathway In Pd Pathogenesismentioning

confidence: 99%

Targeting autophagy using small-molecule compounds to improve potential therapy of Parkinson's disease

Zhang

Zhu

et al. 2021

Acta Pharmaceutica Sinica B

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Parkinson's disease (PD), known as one of the most universal neurodegenerative diseases, is a serious threat to the health of the elderly. The current treatment has been demonstrated to relieve symptoms, and the discovery of new small-molecule compounds has been regarded as a promising strategy. Of note, the homeostasis of the autolysosome pathway (ALP) is closely associated with PD, and impaired autophagy may cause the death of neurons and thereby accelerating the progress of PD. Thus, pharmacological targeting autophagy with small-molecule compounds has been drawn a rising attention so far. In this review, we focus on summarizing several autophagy-associated targets, such as AMPK, mTORC1, ULK1, IMPase, LRRK2, beclin-1, TFEB, GCase, ERR α , C-Abelson, and as well as their relevant small-molecule compounds in PD models, which will shed light on a clue on exploiting more potential targeted small-molecule drugs tracking PD treatment in the near future.

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“…Second, abnormally aggregated α-Syn inclusions are mainly degraded by autophagy (Webb et al, 2003) and defects or deficiency of autophagy can lead to accumulation of intracellular misfolded amyloid α-Syn aggregates, thus causally linking autophagy to PD pathological process (Xilouri et al, 2016;Guo et al, 2020). Third, α-Syn overexpression can impede autophagy by reducing autophagosome formation in human Neuroblastoma SH-SY5Y (Nascimento et al, 2020), and contribute to many different pathologies seen in PD (Winslow and Rubinsztein, 2011). Notably, the pathogenic A53T and A30P α-Syn mutants selectively bound to lysosome-associated membrane protein type 2A (LAMP2A) with high affinity, blocked CMA activity at the LAMP2A level, ultimately resulting in complete damage to this pathway (Cuervo et al, 2004).…”

Section: Caffeine May Modulate Pd Pathology By Regulating Autophagy Amentioning

confidence: 99%

Caffeine and Parkinson’s Disease: Multiple Benefits and Emerging Mechanisms

2020

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Parkinson’s disease (PD) is the second most common neurodegenerative disorder, characterized by dopaminergic neurodegeneration, motor impairment and non-motor symptoms. Epidemiological and experimental investigations into potential risk factors have firmly established that dietary factor caffeine, the most-widely consumed psychoactive substance, may exerts not only neuroprotective but a motor and non-motor (cognitive) benefits in PD. These multi-benefits of caffeine in PD are supported by convergence of epidemiological and animal evidence. At least six large prospective epidemiological studies have firmly established a relationship between increased caffeine consumption and decreased risk of developing PD. In addition, animal studies have also demonstrated that caffeine confers neuroprotection against dopaminergic neurodegeneration using PD models of mitochondrial toxins (MPTP, 6-OHDA, and rotenone) and expression of α-synuclein (α-Syn). While caffeine has complex pharmacological profiles, studies with genetic knockout mice have clearly revealed that caffeine’s action is largely mediated by the brain adenosine A2A receptor (A2AR) and confer neuroprotection by modulating neuroinflammation and excitotoxicity and mitochondrial function. Interestingly, recent studies have highlighted emerging new mechanisms including caffeine modulation of α-Syn degradation with enhanced autophagy and caffeine modulation of gut microbiota and gut-brain axis in PD models. Importantly, since the first clinical trial in 2003, United States FDA has finally approved clinical use of the A2AR antagonist istradefylline for the treatment of PD with OFF-time in Sept. 2019. To realize therapeutic potential of caffeine in PD, genetic study of caffeine and risk genes in human population may identify useful pharmacogenetic markers for predicting individual responses to caffeine in PD clinical trials and thus offer a unique opportunity for “personalized medicine” in PD.

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α-Synuclein Overexpression Induces Lysosomal Dysfunction and Autophagy Impairment in Human Neuroblastoma SH-SY5Y

Cited by 31 publications

References 67 publications

Acidic nanoparticles protect against α‐synuclein‐induced neurodegeneration through the restoration of lysosomal function

Acidic nanoparticles protect against α‐synuclein‐induced neurodegeneration through the restoration of lysosomal function

Targeting autophagy using small-molecule compounds to improve potential therapy of Parkinson's disease

Caffeine and Parkinson’s Disease: Multiple Benefits and Emerging Mechanisms

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