Involvement of 4-hydroxy-2-nonenal Accumulation in Multiple System Atrophy

Abstract

Recent studies have suggested implications for α-synuclein cytotoxicity in the pathomechanism of multiple system atrophy (MSA). Given in vitro evidence that α-synuclein generates oxidative stress, it is proposed that lipid peroxidation may be accelerated in MSA. To address this issue, we performed an immunohistochemical analysis of protein-bound 4-hydroxy-2-nonenal (P-HNE) in sections of archival, formalin-fixed, paraffin-embedded pontine materials of eight sporadic MSA patients and eight age-matched control subjects. In the MSA cases, P-HNE immunoreactivity was localized in all of the neuronal cytoplasmic inclusions and glial cytoplasmic inclusions, both of them identified with α-synuclein and ubiquitin. It was also detectable in reactive astrocytes and phagocytic microglia but undetectable in activated microglia. By contrast, P-HNE immunoreactivity in the control cases was only very weak or not at all in the parenchyma including neurons and glia. The present results provide in vivo evidence that HNE participates in α-synuclein-induced cytotoxicity and neuroinflammation in MSA.

Lipid Peroxidation Product 4-Hydroxy-2-Nonenal Promotes Seeding-Capable Oligomer Formation and Cell-to-Cell Transfer of α-Synuclein

“…HNE-modified proteins are accumulated in the brainstem and cortical-type Lewy bodies in PD and DLB (5,52), as well as in glial and neuronal inclusion bodies in multiple system atrophy (46). Additionally, the modification of a-synuclein by malondialdehyde, another common lipid peroxidation product, was observed in the frontal cortices and the substantia nigra in PD and DLB patients (7).…”

Region‐Specific Alterations of Matrix Metalloproteinase Activity in Multiple System Atrophy

“…The mechanisms underlying increased MMP-2 activity and increased MMP-1, MMP-2, and MMP-3 expression in MSA patients remain unknown, yet MMPs have been found to be activated by cytokines, reactive oxygen species, nitric oxide, and other neuroinflammatory triggers, factors that are commonly increased in MSA. 7,8,[11][12][13]55 MMP-2 and, to a lesser extent, MMP-3 and MMP-1 are expressed in neutrophils, macrophages, and resident glia of the brain. 17,18,51,56 Interestingly, type IV collagen, the main substrate of MMP-2 and MMP-9, is decreased in MSA patients.…”

“…Considered as a primary oligodendrogliopathy, the cytopathological hallmark of the disorder is the accumulation of alpha‐synuclein (α‐Syn) protein aggregates in oligodendrocytes forming glial cytoplasmic inclusions (GCIs) . MSA is also characterized by secondary neuronal loss and myelin alteration, as well as blood–brain barrier (BBB) dysfunction, neuroinflammation, microglial activation, and oxidative stress …”

“…3 MSA is also characterized by secondary neuronal loss and myelin alteration, [4][5][6] as well as blood-brain barrier (BBB) dysfunction, neuroinflammation, microglial activation, and oxidative stress. [7][8][9][10][11][12][13] Given that the mechanisms underlying secondary neuronal and myelin alteration in MSA are still poorly understood, several lines of evidence suggest a potential involvement of matrix metalloproteinases (MMPs), a group of zinc-dependent endopeptidases known for their capacity to degrade several components of the extracellular matrix and basement membranes. [14][15][16] In addition to their involvement in many physiological processes requiring extracellular remodeling, such as cell differentiation and migration or angiogenesis, MMPs may also contribute to various pathological processes.…”

Deuterium Protection of Polyunsaturated Fatty Acids against Lipid Peroxidation

“…There is evidence suggesting that the oligomerization and stabilization is, at least in part, driven by reactive carbonyls such as HNE and 4-oxo-2-nonenal (ONE) (Qin et al, 2006;Selley et al, 1998;Shibata et al, 2010;Nasstrom et al, 2011). There is evidence suggesting that the oligomerization and stabilization is, at least in part, driven by reactive carbonyls such as HNE and 4-oxo-2-nonenal (ONE) (Qin et al, 2006;Selley et al, 1998;Shibata et al, 2010;Nasstrom et al, 2011).…”