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

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.

Design and evaluation of bi-functional iron chelators for protection of dopaminergic neurons from toxicants

“…Moreover, it indicates new strategies to develop brain-targeted metal chelators. Iron chelators have been deemed therapeutically useful in PD and other neurodegenerative conditions (Dunaief 2011;Joppe et al 2019;Kaindlstorfer et al 2018;Ndayisaba et al 2019). However, their exact effects on brain pathophysiology have not been fully elucidated.…”

Multiple System Atrophy: An Oligodendroglioneural Synucleinopathy1

“…Iron can convert native αS into a β-sheet conformation and promotes/accelerates its aggregation either directly or via increasing levels of oxidative stress. Interestingly, αS has been identified to have a ferrireductase activity and an iron-regulated element on mRNA level, implying a direct interaction between iron and αS [ 302 ].…”

“…TfR expression was unchanged in pons and SN in PD, MSA, and controls, while putamen showed decreased TfR expression in PD compared to controls and MSA. The results of this study suggest that neurodegeneration is accompanied by region-specific differences in iron dysregulation which might be regarded as disease specific patterns in MSA, where limited iron export coupled with an increase in ferritin iron load results in decreased bioavailability of iron in MSA pons [ 302 ]. A dysregulation of iron export coupled with an increase in ferritin iron was detected to a lesser extent also in putamen.…”

“…Although it is still unclear whether iron accumulation is rather a consequence and secondary event in the cascade of neuronal degeneration than a primary cause. Correlating the severity of putamen atrophy and iron accumulation suggests that iron accumulation is a secondary effect of neurodegeneration as significantly increased iron in the putamen is associated with advanced atrophy compared to moderate iron accumulation in globus pallidus along with less severe atrophy [ 302 ].…”

Lentiform Nucleus Hyperechogenicity in Parkinsonian Syndromes: A Systematic Review and Meta-Analysis with Consideration of Molecular Pathology

“…For PD, an iron overload with its inherent toxicity for dopaminergic neurons of the SN is assumed to play an important role in the disease pathogenesis [40]. Concerning MSA and PSP, pathological studies have demonstrated an increase of iron levels in the putamen and globus pallidus but also in the SN [47,48]. So far, there are no studies investigating the cellular and extracellular changes in PD patients with LN hyperechogenicity.…”