| First Author | Kim Y | Year | 2020 |
| Journal | J Neurochem | Volume | 155 |
| Issue | 2 | Pages | 177-190 |
| PubMed ID | 32574378 | Mgi Jnum | J:297521 |
| Mgi Id | MGI:6473041 | Doi | 10.1111/jnc.15107 |
| Citation | Kim Y, et al. (2020) H63D variant of the homeostatic iron regulator (HFE) gene alters alpha-synuclein expression, aggregation, and toxicity. J Neurochem 155(2):177-190 |
| abstractText | Pathological features of Parkinson's disease include the formation of Lewy bodies containing alpha-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 alpha-synuclein aggregation. This study examines the effects of commonly occurring H63D variant of the homeostatic iron regulatory (HFE) gene on alpha-synuclein pathology in cell culture and animal models. H63D HFE expression in SH-SY5Y cells lowered endogenous alpha-synuclein levels and significantly decreased pre-formed fibril-induced alpha-synuclein aggregation. H63D HFE cells were also protected from pre-formed fibril-induced apoptosis. Autophagic flux, a major pathway for alpha-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 x 129 mice showed less alpha-synuclein aggregation and less decline in motor function compared to WT Hfe. Collectively, this study suggests that H63D HFE variant modifies alpha-synuclein pathology through the induction of autophagy and has the potential to impact the pathogenesis and treatment response in Parkinson's disease. |
