Abstract
Parkinson’s disease (PD) is a neurodegenerative disease characterized by selective dopaminergic (DAergic) neuronal degeneration in the substantia nigra (SN) and proteinaceous α-synuclein-positive Lewy bodies and Lewy neuritis. As a chemical chaperone to promote protein stability and an autophagy inducer to clear aggregate-prone proteins, a disaccharide trehalose has been reported to alleviate neurodegeneration in PD cells and mouse models. Its trehalase-indigestible analogs, lactulose and melibiose, also demonstrated potentials to reduce abnormal protein aggregation in spinocerebellar ataxia cell models. In this study, we showed the potential of lactulose and melibiose to inhibit α-synuclein aggregation using biochemical thioflavin T fluorescence, cryogenic transmission electron microscopy (cryo-TEM) and prokaryotic split Venus complementation assays. Lactulose and melibiose further reduced α-synuclein aggregation and associated oxidative stress, as well as protected cells against α-synuclein-induced neurotoxicity by up-regulating autophagy and nuclear factor, erythroid 2 like 2 (NRF2) pathway in DAergic neurons derived from SH-SY5Y cells over-expressing α-synuclein. Our findings strongly indicate the potential of lactulose and melibiose for mitigating PD neurodegeneration, offering new drug candidates for PD treatment.
Highlights
Parkinson’s disease (PD) is the second most common neurodegenerative disorder affecting 1%people older than 60 years old
By measuring thioflavin T fluorescence, we examined fibrillation of α-synuclein in the absence or presence of trehalose and two analogs, lactulose and melibiose (Figure 1) using the recombinant synuclein alpha (SNCA)-His protein produced in E. coli (Figure 2A)
The α-synuclein α-synuclein is prone lines of of evidence have shown thethe important role of misfolded α-synuclein in the pathogenesis of and degradation of misfolded important role of α-synuclein in the pathogenesis of PD [42] and degradation of misfolded α-synuclein to to be be oneone of the strategies for PD
Summary
Parkinson’s disease (PD) is the second most common neurodegenerative disorder affecting 1%people older than 60 years old. The symptoms commonly seen in PD patients are resting tremor, rigidity, bradykinesia and postural instability. These symptoms result predominantly from a massive loss of dopaminergic (DAergic) neurons located in the pars compacta of the substantia nigra (SN). Duplication, triplication and point mutations of synuclein alpha (SNCA) gene cause the familial parkinsonian phenotype, implicating that accumulated conformation-changed α-synuclein causes detrimental effects to neurons [2]. The α-synuclein tends to form oligomers, fibrils and aggregates, which have been considered the culprits to cause neurotoxicity [3,4,5,6]. The disease etiology remains to be clarified, proteins of PD-causing genes such as SNCA, parkin RBR E3 ubiquitin protein ligase (PRKN), DJ1
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Disclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.