This paper below is listed on ATH home page, it is a free paper from last year. An open question of these authors was if accumulating iron was a primary or secondary event in the pathogenesis of MSA. The mouse study ATH did almost 2 years ago with "robust" findings supported the essential role of iron in the pathogenesis as did also the only PBT434 paper. Now we have more knowledge about iron overload and mitochondria, which I posted just yesterday (He H et al, 2019). The papers about Sirt3 regulation of mitochondria and the paper on how DJ-1 regulates ER-mitochondrion association ( look at my posters on 30th of Nov) give more support to regard iron as a primary cause in the pathogenesis of MSA and in general in PD and that PBT434 would work.
We are not yet there but closer! Iron overload seems clear to have a central role in the pathogenesis of PD, at least in my opinion.

The Relevance of Iron in the Pathogenesis of Multiple System Atrophy: A Viewpoint.

Kaindlstorfer C¹, Jellinger KA², Eschlböck S¹, Stefanova N¹, Weiss G³, Wenning GK¹.

Author information

1

Department of Neurology, Medical University of Innsbruck, Innsbruck, Austria.

2

Institute of Clinical Neurobiology, Vienna, Austria.

3

Department of Internal Medicine, Medical University of Innsbruck, Innsbruck, Austria.

Abstract

Iron is essential for cellular development and maintenance of multiple physiological processes in the central nervous system. The disturbance of its homeostasis leads to abnormal iron deposition in the brain and causes neurotoxicity via generation of free radicals and oxidative stress. Iron toxicity has been established in the pathogenesis of Parkinson's disease; however, its contribution to multiple system atrophy (MSA) remains elusive. MSA is characterized by cytoplasmic inclusions of misfolded α-synuclein (α-SYN) in oligodendrocytes referred to as glial cytoplasmic inclusions (GCIs). Remarkably, the oligodendrocytes possess high amounts of iron, which together with GCI pathology make a contribution toward MSA pathogenesis likely. Consistent with this observation, the GCI density is associated with neurodegeneration in central autonomic networks as well as olivopontocerebellar and striatonigral pathways. Iron converts native α-SYN into a β-sheet conformation and promotes its aggregation either directly or via increasing levels of oxidative stress. Interestingly, α-SYN possesses ferrireductase activity and α-SYN expression underlies iron mediated translational control via RNA stem loop structures. Despite a correlation between progressive putaminal atrophy and iron accumulation as well as clinical decline, it remains unclear whether pathologic iron accumulation in MSA is a secondary event in the cascade of neuronal degeneration rather than a primary cause. This review summarizes the current knowledge of iron in MSA and gives evidence for perturbed iron homeostasis as a potential pathogenic factor in MSA-associated neurodegeneration.