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

BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR BASIS OF DISEASE

卷:1862

Article

Zhu, Zhou-Jing¹  Wu, Ka-Chun¹  Yung, Wing-Ho¹  Qian, Zhong-Ming²  Ke, Ya¹ 

[1] Chinese Univ Hong Kong, Fac Med, Sch Biomed Sci, Shatin, Hong Kong, Peoples R China

[2] Fudan Univ, Sch Pharm, Neuropharmacol Lab, 826 Zhang Heng Rd, Shanghai 201203, Peoples R China

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

DOI  :  10.1016/j.bbadis.2016.01.002

来源: Elsevier

【 摘 要 】

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. (C) 2016 Elsevier B.V. All rights reserved.

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