Dynamic modeling of α-synuclein aggregation in dopaminergic neuronal system indicates points of neuroprotective intervention: Experimental validation with implications for Parkinson's therapy

Z. Sultana, K. E. Paleologou, K. M. Al-Mansoori, M. T. Ardah, N. Singh, S. Usmani, H. Jiao, F. L. Martin, M. M S Bharath, S. Vali, Omar Ali El-Agnaf

Research output: Contribution to journalArticle

11 Citations (Scopus)

Abstract

Protein aggregation is the major pathological hallmark seen in neurodegenerative disorders such as Parkinson's disease (PD). Alpha-synuclein (αS) is the main component of protein aggregates that form Lewy bodies (LBs) in PD and dementia with LBs. There have been several attempts to intervene in the process of expression, modification, clearance, and aggregation of αS as a therapeutic strategy toward neuroprotection. In this study, we have employed a novel, predictive, system level approach in silico to study four different strategies of anti-aggregation therapies: (a) reduction in αS modifications such as phosphorylation, nitration, or truncation in an approach called "seed clearance;" (b) "anti-oligomerization" approach through blocking the early oligomers formation; (c) "oligomers clearance" process by increasing its lysosomal degradation; and (d) "anti-aggregation" that involves prevention of aggregate formation at a later stage. These strategies were tested in a virtual dopaminergic neuronal system triggered by overexpression (OE) of mutant αS-A53T with or without rotenone (Rot)-induced oxidative stress. The results were compared by analyzing markers related to various end points such as oxidative stress, dopamine (DA) metabolism, proteasome function, survival and apoptosis. The experimental system and anti-oligomerization strategies were recapitulated in vitro in M17 dopaminergic cells overexpressing mutant αS-A53T triggered with Cu(II)-mediated oxidative stress, and the experimental data prospectively corroborated with the predictive results. Through this analysis, we found that intervention in the early part of the aggregation pathway by prevention of oligomer formation and increased clearance is indeed a good neuroprotective strategy, whereas anti-aggregation efforts to break up the aggregate at later stages has negative effects on the system.

Original languageEnglish
Pages (from-to)303-317
Number of pages15
JournalNeuroscience
Volume199
DOIs
Publication statusPublished - 29 Dec 2011
Externally publishedYes

Fingerprint

Synucleins
Oxidative Stress
Parkinson Disease
Lewy Body Disease
Rotenone
alpha-Synuclein
Proteasome Endopeptidase Complex
Neurodegenerative Diseases
Computer Simulation
Dopamine
Seeds
Therapeutics
Phosphorylation
Apoptosis
Proteins

Keywords

  • α-synuclein
  • Dopaminergic neuron
  • In silico
  • Oligomers
  • Parkinson's disease
  • Protein aggregation

ASJC Scopus subject areas

  • Neuroscience(all)

Cite this

Dynamic modeling of α-synuclein aggregation in dopaminergic neuronal system indicates points of neuroprotective intervention : Experimental validation with implications for Parkinson's therapy. / Sultana, Z.; Paleologou, K. E.; Al-Mansoori, K. M.; Ardah, M. T.; Singh, N.; Usmani, S.; Jiao, H.; Martin, F. L.; Bharath, M. M S; Vali, S.; Ali El-Agnaf, Omar.

In: Neuroscience, Vol. 199, 29.12.2011, p. 303-317.

Research output: Contribution to journalArticle

Sultana, Z. ; Paleologou, K. E. ; Al-Mansoori, K. M. ; Ardah, M. T. ; Singh, N. ; Usmani, S. ; Jiao, H. ; Martin, F. L. ; Bharath, M. M S ; Vali, S. ; Ali El-Agnaf, Omar. / Dynamic modeling of α-synuclein aggregation in dopaminergic neuronal system indicates points of neuroprotective intervention : Experimental validation with implications for Parkinson's therapy. In: Neuroscience. 2011 ; Vol. 199. pp. 303-317.
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AU - Singh, N.

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