This paper below is important because it explains more about the role of iron in the 2 types of MSA. Now when we are so near to getting the open study results, the difference between the types of MSA does not matter to us ATH investors. However, their results beautifully support that iron chelators should positively affect the disease process. So these Canadian authors expect that the next-generation iron chelation strategy will get better results than the deferiprone study (Devos et al 2022).
This is what we have with ATH434, a new type of iron chelator that does not harm the mitochondria of the neurons (Prof. Kosman's poster) and an iron chelator that works like the physiological iron chelator ( Dr. Pall's poster). Now we need to wait a few weeks to see if works not only in theory and animal models but also in human MSA.Cellular iron deposition patterns predict clinical subtypes of multiple system atrophy
AffiliationsDOI: 10.1016/j.nbd.2024.106535Free article
- PMID: 38761956
Abstract
Background: Multiple system atrophy (MSA) is a primary oligodendroglial synucleinopathy, characterized by elevated iron burden in early-affected subcortical nuclei. Although neurotoxic effects of brain iron deposition and its relationship with α-synuclein pathology have been demonstrated, the exact role of iron dysregulation in MSA pathogenesis is unknown. Therefore, advancing the understanding of iron dysregulation at the cellular level is critical, especially in relation to α-synuclein cytopathology.
Methods: Iron burden in subcortical and brainstem regions were histologically mapped in human post-mortem brains of 4 MSA-parkinsonian (MSA-P), 4 MSA-cerebellar (MSA-C), and 1 MSA case with both parkinsonian and cerebellar features. We then performed the first cell type-specific evaluation of pathological iron deposition in α-synuclein-affected and -unaffected cells of the globus pallidus, putamen, and the substantia nigra, regions of highest iron concentration, using a combination of iron staining with immunolabelling. Selective regional and cellular vulnerability patterns of iron deposition were compared between disease subtypes. In 7 MSA cases, expression of key iron- and closely related oxygen-homeostatic genes were examined.
Results: MSA-P and MSA-C showed different patterns of regional iron burden across the pathology-related systems. We identified subcortical microglia to predominantly accumulate iron, which was more distinct in MSA-P. MSA-C showed relatively heterogenous iron accumulation, with greater or similar deposition in astroglia. Iron deposition was also found outside cellular bodies. Cellular iron burden associated with oligodendrocytic, and not neuronal, α-synuclein cytopathology. Gene expression analysis revealed dysregulation of oxygen homeostatic genes, rather than of cellular iron. Importantly, hierarchal cluster analysis revealed the pattern of cellular vulnerability to iron accumulation, distinctly to α-synuclein pathology load in the subtype-related systems, to distinguish MSA subtypes.
Conclusions: Our comprehensive evaluation of iron deposition in MSA brains identified distinct regional, and for the first time, cellular distribution of iron deposition in MSA-P and MSA-C and revealed cellular vulnerability patterns to iron deposition as a novel neuropathological characteristic that predicts MSA clinical subtypes. Our findings suggest distinct iron-related pathomechanisms in MSA clinical subtypes that are therefore not a consequence of a uniform down-stream pathway to α-synuclein pathology, and inform current efforts in iron chelation therapies at the disease and cellular-specific levels.
Keywords: Alpha-synuclein; Atypical parkinsonism; Iron; Microglia; Multiple system atrophy; Neurodegeneration.
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This paper below is important because it explains more about the...
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