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Biochim Biophys Acta. 2016 Apr;1862(4):518-525. doi: 10.1016/j.bbadis.2016.01.002. Epub 2016 Jan 6.

Differential interaction between iron and mutant alpha-synuclein causes distinctive Parkinsonian phenotypes in Drosophila.

Author information

1
School of Biomedical Sciences, Faculty of Medicine, The Chinese University of Hong Kong, NT, Hong Kong.
2
Laboratory of Neuropharmacology, Fudan University School of Pharmacy, 826 Zhang Heng Road, Pu Dong, Shanghai 201203, China. Electronic address: qianzhongming@fudan.edu.cn.
3
School of Biomedical Sciences, Faculty of Medicine, The Chinese University of Hong Kong, NT, Hong Kong. Electronic address: yake@cuhk.edu.hk.

Abstract

Alpha-synuclein aggregation is the central hallmark of both sporadic and familial Parkinson's disease (PD). Patients with different PD-causing genetic defects of alpha-synuclein usually show distinctive clinical features that are atypical to sporadic PD. Iron accumulation is invariably found in PD. Recent studies showed that mutant and wild-type alpha-synuclein may have differential interaction with iron and mutant alpha-synuclein toxicity could be preferentially exacerbated by iron. We hence hypothesized that iron overload could selectively influence mutant alpha-synuclein toxicity and disease phenotypes. To test the hypothesis, we investigated if Drosophila melanogaster over-expressing A53T, A30P, and wild-type (WT) alpha-synuclein have different responses to iron treatment. We showed that iron treatment induced similar reduction of survival rate in all flies but induced a more severe motor decline in A53T and A30P mutant alpha-synuclein expressing flies, suggesting interaction between mutant alpha-synuclein and iron. Although no significant difference in total head iron content was found among these flies, we demonstrated that iron treatment induced selective DA neuron loss in motor-related PPM3 cluster only in the flies that express A53T and A30P mutant alpha-synuclein. We provided the first in vivo evidence that iron overload could induce distinctive neuropathology and disease phenotypes in mutant but not WT alpha-synuclein expressing flies, providing insights to the cause of clinical features selectively exhibited by mutant alpha-synuclein carriers.

KEYWORDS:

A53T and A30P; Alpha-synuclein; Dopaminergic neuron; Drosophila melanogaster; Iron; Parkinson's disease

PMID:
26769358
DOI:
10.1016/j.bbadis.2016.01.002
[Indexed for MEDLINE]
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