H63D variant of the homeostatic iron regulator (HFE) gene alters α-synuclein expression, aggregation, and toxicity

Yunsung Kim; Mark C. Stahl; Xuemei Huang; James R. Connor

H63D variant of the homeostatic iron regulator (HFE) gene alters α-synuclein expression, aggregation, and toxicity

Pathological features of Parkinson's disease include the formation of Lewy bodies containing α‐synuclein and the accumulation of iron in the substantia nigra. Previous studies have suggested that iron accumulation contributes to the Parkinson's disease pathology through reactive oxygen species production and accelerated α‐synuclein aggregation. This study examines the effects of commonly occurring H63D variant of the homeostatic iron regulatory (HFE) gene on α‐synuclein pathology in cell culture and animal models. H63D HFE expression in SH‐SY5Y cells lowered endogenous α‐synuclein levels and significantly decreased pre‐formed fibril‐induced α‐synuclein aggregation. H63D HFE cells were also protected from pre‐formed fibril‐induced apoptosis. Autophagic flux, a major pathway for α‐synuclein clearance, was increased in H63D HFE cells. Expression of REDD1 was elevated and rapamycin treatment was unable to further induce autophagy, indicating mTORC1 inhibition as the main mechanism of autophagy induction. Moreover, siRNA knockdown of REDD1 in H63D HFE cells decreased autophagic flux and increased the sensitivity to PFF‐mediated toxicity. While iron chelator (deferiprone) treatment rescued WT HFE cells from pre‐formed fibril toxicity, it exacerbated or was unable to rescue H63D HFE cells. In the in vivo pre‐formed fibril intracranial injection model, H67D Hfe (mouse homolog of the human H63D HFE variant) C57BL/6J × 129 mice showed less α‐synuclein aggregation and less decline in motor function compared to WT Hfe. Collectively, this study suggests that H63D HFE variant modifies α‐synuclein pathology through the induction of autophagy and has the potential to impact the pathogenesis and treatment response in Parkinson's disease.

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Metadata

Work Title	H63D variant of the homeostatic iron regulator (HFE) gene alters α-synuclein expression, aggregation, and toxicity
Access	Open Access
Creators	Yunsung Kim Mark C. Stahl Xuemei Huang James R. Connor
License	In Copyright (Rights Reserved)
Work Type	Article
Publisher	Journal of Neurochemistry
Publication Date	June 23, 2020
Publisher Identifier (DOI)	10.1111/jnc.15107
Deposited	March 17, 2021

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H63D variant of the homeostatic iron regulator (HFE) gene alters α-synuclein expression, aggregation, and toxicity

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View: alphaSynHFE_manuscript_FINAL2.docx

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View: Figure4_CellDeath.tiff

View: Figure5_LC3Baseline.tiff

View: Figure6_REDD1.tiff

View: Figure7_DFP.tiff

View: Figure8_MousePFFInjection.tiff

View: Supplemental_figures.docx

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H63D variant of the homeostatic iron regulator (HFE) gene alters α-synuclein expression, aggregation, and toxicity

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