Modulation of α‐synuclein aggregation by dopamine in the presence of MPTP and its metabolite

Jethva, Prashant N.; Kardani, Jay; Roy, Ipsita

doi:10.1111/j.1742-4658.2011.08093.x

Cited by 34 publications

(26 citation statements)

References 42 publications

(62 reference statements)

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“…Previously, there have been conflicting reports concerning the effect of dopamine on the aggregation/fibrillization of AS . It would appear that, under some conditions, dopamine can inhibit aggregation , and that, under other conditions, it can promote aggregation . At present, it is not clear how these results relate to the situation in vivo .…”

Section: Discussionmentioning

confidence: 97%

Cu(II) and dopamine bind to α‐synuclein and cause large conformational changes

et al. 2014

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a-Synuclein (AS) is an intrinsically disordered protein that can misfold and aggregate to form Lewy bodies in dopaminergic neurons, a classic hallmark of Parkinson's disease. The binding of Cu(II) and dopamine to AS was evaluated by nanopore analysis with a-hemolysin. In the absence of Cu(II), wild-type AS (1 lM) readily translocated through the pore with a blockade current of À 85 pA, but mostly bumping events were observed in the presence of 25 lM Cu(II). A binding site in the N-terminus was confirmed, because Cu(II) had no effect on the event profile of a peptide consisting of the C-terminal 96-140 residues. In the presence of dopamine (25 lM), the translocation events at À 85 pA shifted to À 80 pA, which also represents translocation events, because the event time decreases with increasing voltage. Events at À 80 pA were also observed for the mutant A30P AS in the presence of dopamine. Event profiles for an N-terminal 1-60-residue peptide and a C-terminal 96-140-residue peptide were both altered in the presence of 25 lM dopamine. In contrast, dopamine had little effect on the CD spectrum of AS, and a single binding site with a K a of 3.5 9 10 3 M À1 was estimated by isothermal titration calorimetry. Thus, dopamine can interact with both the N-terminus and the C-terminus. Two-dimensional NMR spectroscopy of AS in the presence of dopamine showed that there were significant changes in the spectra in all regions of the protein. According to these findings, a model is presented in which dopamine induces folding between the N-terminus and C-terminus of AS. Partially folding conformations such as this may represent important intermediates in the misfolding of AS that leads to fibrillization.

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Section: Discussionmentioning

confidence: 97%

Cu(II) and dopamine bind to α‐synuclein and cause large conformational changes

et al. 2014

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“…Several studies have already noted a connection between SNCA and MPP + [42]. MPP + was found to accelerate the rate of SNCA aggregation [43]. Similarly, SNCA exhibited striking resistance to MPTP-induced apoptosis [44] and was highly expressed in the nigrostriatal pathway of normal mice following MPP +induced injury [45].…”

Section: Discussionmentioning

confidence: 99%

Characterization of Polyethylene Glycol‐Polyethyleneimine as a Vector for Alpha‐Synuclein siRNA Delivery to PC12 Cells for Parkinson's Disease

Liu

Yang

et al. 2013

CNS Neurosci Ther

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“…Aggregation kinetics was followed by fitting the data using the formula 28,29 :

y = y_{i} + {mx}_{i} + \frac{y_{f} + {mx}_{f}}{1 + e^{\frac{x - x_{normalo}}{τ}}},

where y i + mx i is the initial line, y f + mx f is the final line, and x 0 is the midpoint of maximum signal. The apparent rate constant ( k app ) is 1/ τ and lag time is calculated to be x 0 –2 τ .…”

Section: Methodsmentioning

confidence: 99%

Stabilization of elongated polyglutamine tracts by a helical peptide derived from N‐terminal huntingtin

Sethi

Roy

2020

IUBMB Life

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In Huntington's disease, the length of the polyglutamine tract in the mutant protein correlates positively with the formation of aggregates and disease symptoms and severity of the disease. Some disease‐modifying factors exist. However, no organized study has been carried out to investigate the effect of polyglutamine length in the mutant protein on the efficacy of a therapeutic strategy. We had shown earlier that the helical peptide arising out of the N‐terminal stretch of normal huntingtin is able to inhibit aggregation of a number of proteins, including luciferase, α‐synuclein, p53, and Rnq1. In this work, we show that polyglutamine stretches of differing lengths, namely 51Q, 72Q, and 103Q, form a mixture of aggregates at different rates, with the rate increasing in a polyQ length‐dependent manner. The helical peptide is able to inhibit the rate of aggregation. The extent of inhibition was different when measuring either total aggregation or only fibrillar aggregates, suggesting that the helical peptide with benign polyQ stretch alters the aggregation landscape of different elongated polyQ lengths differently. Our results suggest that designing a therapeutic approach to inhibit protein aggregation must take note of polyQ length of the protein.

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Modulation of α‐synuclein aggregation by dopamine in the presence of MPTP and its metabolite

Cited by 34 publications

References 42 publications

Cu(II) and dopamine bind to α‐synuclein and cause large conformational changes

Cu(II) and dopamine bind to α‐synuclein and cause large conformational changes

Characterization of Polyethylene Glycol‐Polyethyleneimine as a Vector for Alpha‐Synuclein siRNA Delivery to PC12 Cells for Parkinson's Disease

Stabilization of elongated polyglutamine tracts by a helical peptide derived from N‐terminal huntingtin

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