Host oligodendrogliopathy and α-synuclein strains dictate disease severity in multiple system atrophy

Abstract

Multiple system atrophy is a progressive neurodegenerative disease with prominent autonomic and motor features. During early stages different subtypes of multiple system atrophy are distinguished by their predominant parkinsonian or cerebellar symptoms reflecting the heterogeneous nature of the disease. The pathognomonic feature of multiple system atrophy is the presence of ɑ-synuclein (ɑSyn) protein deposits in oligodendroglial cells. ɑSyn can assemble in specific cellular or disease environments and form ɑSyn strains with unique structural features but the ability of ɑSyn strains to propagate in oligodendrocytes remains elusive. More recently, it was shown that multiple multiple system atrophy strains with related conformations exist in the brain of patients. Here, we investigated if different ɑSyn strains can influence multiple system atrophy progression in a strain-dependent manner. To this aim, we injected two recombinant ɑSyn strains (fibrils and ribbons) in multiple system atrophy transgenic mice and found that ɑSyn protein strains determine disease severity in multiple system atrophy via host-restricted and cell-specific pathology in vivo. ɑSyn strains significantly impact disease progression in a strain-dependent way via oligodendroglial, neurotoxic and immune-related mechanisms. Neurodegeneration and brain atrophy were accompanied by unique microglial and astroglial responses and the recruitment of central and peripheral immune cells. The differential activation of microglial cells correlated with the structural features of ɑSyn strains both in vitro and in vivo. Spectral analysis showed that ribbons propagate oligodendroglial inclusions that are structurally distinct from those of fibrils, with resemblance to oligodendroglial inclusions in multiple system atrophy patient brain. This study therefore shows that the multiple system atrophy phenotype is governed by both the ɑSyn strain nature and the host environment and that by injecting ɑSyn strains in a multiple system atrophy animal model a more comprehensive phenotype can be established.

A Mouse Model of Multiple System Atrophy: Bench to Bedside

“…The general notion from an increasing number of studies using a-syn spreading models confirms that healthy oligodendrocytes are not readily accumulating fibrillar a-syn in their cytoplasm and possibly a preceding oligodendroglial dysfunction is needed to trigger the GCI formation. This has been supported by a recent experiment, in which only transgenic mice with oligodendroglial a-syn overexpression which get intracerebral inoculation of a-syn polymorphs are prone to accelerating an MSA-like phenotype in a strain-dependent manner [73]. The a-syn spreading models are crucial for understanding the specific features of protein misfolding and properties in MSA versus other synucleinopathies, and thus shed light on pathogenic mechanisms involved in the progression of the disease [74].…”

Urinary tract infections trigger synucleinopathy via the innate immune response

“…These spinal tracts are among the earliest to be affected in MSA and connect the urogenital nerves and the spinal cord to the midbrain and cerebellum. Since the propagation of ɑSyn in MSA requires the expression of oligodendroglial ɑSyn [52,62], we used a humanized ɑSyn model (hu-ɑSyn mice) to study MSA progression. Hu-ɑSyn mice lack murine ɑSyn and only express human ɑSyn, at levels comparable to those seen in WT mice [20].…”

“…Oligodendrocytes normally express low levels of ɑSyn [3,13,14,28]. Aggregation of ɑSyn in oligodendrocytes leads to the assembly of disease-specific ɑSyn fibrils with highly aggregation-prone features [52,62]. In MSA patients, aggregates of ɑSyn are also detected in spinal cord oligodendrocytes and Schwann cells of the spinal nerves [6,42].…”

A Dual Synergetic Nanoreactor for Managing Parkinson's Disease by Regulating Inflammation and Mitigating Oxidative Damage

“…[27] The effect of Ptzyme alone is not sufficient for achieving wholistic disease therapy, as it has defects in achieving mild regulation of the inflammatory microenvironment. [28][29][30] Microglia has been implicated in the regulation of inflammatory microenvironment in the brain, thus playing cardinal part in regulating the development, homeostasis, and degeneration of the central nervous system (CNS). [31,32] Studies have found that under the treatment of anti-inflammation small molecule compounds like quercetin (Que), the microglia could switch from pro-inflammatory M1 phenotype to the anti-inflammatory M2phenotype, thus affording a desirable solution for regulating inflammatory microenvironment.…”