Multiple system atrophy: α-Synuclein strains at the neuron-oligodendrocyte crossroad

Abstract

The aberrant accumulation of α-Synuclein within oligodendrocytes is an enigmatic, pathological feature specific to Multiple system atrophy (MSA). Since the characterization of the disease in 1969, decades of research have focused on unravelling the pathogenic processes that lead to the formation of oligodendroglial cytoplasmic inclusions. The discovery of aggregated α-Synuclein (α-Syn) being the primary constituent of glial cytoplasmic inclusions has spurred several lines of research investigating the relationship between the pathogenic accumulation of the protein and oligodendrocytes. Recent developments have identified the ability of α-Syn to form conformationally distinct "strains" with varying behavioral characteristics and toxicities. Such "strains" are potentially disease-specific, providing insight into the enigmatic nature of MSA. This review discusses the evidence for MSA-specific α-Syn strains, highlighting the current methods for detecting and characterizing MSA patient-derived α-Syn. Given the differing behaviors of α-Syn strains, we explore the seeding and spreading capabilities of MSA-specific strains, postulating their influence on the aggressive nature of the disease. These ideas culminate into one key question: What causes MSA-specific strain formation? To answer this, we discuss the interplay between oligodendrocytes, neurons and α-Syn, exploring the ability of each cell type to contribute to the aggregate formation while postulating the effect of additional variables such as protein interactions, host characteristics and environmental factors. Thus, we propose the idea that MSA strain formation results from the intricate interrelation between neurons and oligodendrocytes, with deficits in each cell type required to initiate α-Syn aggregation and MSA pathogenesis.

Keywords: Alpha-synuclein; Glial cytoplasmic inclusion; Multiple system atrophy; Oligodendrocytes; Oligodendroglial proteinopathy; Protein aggregation; Strains; Synucleinopathy.

Fig. 1

Criteria for a categorical diagnosis of Multiple system atrophy with supportive clinical features as set out by the Movement Disorder Society [23]. A diagnosis of Multiple system atrophy (MSA) is defined by four categories – possible prodromal, clinically probable, clinically established and neuropathologically established. Possible prodromal, clinically probable, and clinically established MSA is characterized by the presentation of autonomic, parkinsonian or cerebellar features. Supporting clinical motor and non-motor features aid in determining a clinical diagnosis. Neuropathologically established MSA can only be determined by identifying glial cytoplasmic inclusions during post-mortem analysis of patient brain tissue. Information adapted from Wenning et al., 2022 [23]

Fig. 2

Strain pathology is dependent on strain and host characteristics. The ability of α-Synuclein strains to seed and spread is dictated by the properties of the strain itself in combination with the characteristics of the host. When tested in the same cell lines, Multiple system atrophy (MSA) and Parkinson’s Disease (PD) patient extracts display differing abilities to seed aggregation, with PD extracts only seeding new aggregation via insoluble fractions. In comparison, both insoluble and soluble fractions of MSA extracts were successful in seeding aggregation. Inclusions formed in cells differed in both size and morphology. Injections of MSA extracts into different transgenic mice models highlighted the effects of host characteristics on pathology. In TgM83^+/− mice, inclusion pathology was localized to neurons in the hindbrain, while in Tg(SNCA*A53T^+/+)Nbm (mice expressing A53T human α-Syn on a mouse α-Syn knockout background), the limbic system was affected with neuronal and astrocytic inclusions. Therefore, in synucleinopathies such as MSA, strain characteristics may dictate the propagation of pathology, while host characteristics determine the cell types and brain regions affected

Fig. 3

Multiple system atrophy strain formation requires multiple insults. The formation of Multiple system atrophy-specific α-Synuclein strains is likely a multifactorial process requiring insults to both neurons and oligodendrocytes. Host characteristics and environmental factors may favor the upregulation and secretion of neuronal α-Syn, while the same factors may alter oligodendrocytes providing the necessary cellular environment for strain formation to occur. Additional oligodendrocyte-specific factors may be pivotal in determining the unique characteristics of Multiple system atrophy-specific strains. Once formed, these strains may induce glial cytoplasmic inclusions in oligodendrocytes or may be shuttled to neurons resulting in neuronal cytoplasmic inclusions

Fig. 4

Proposed pathogenesis of Multiple system atrophy. Following insults to neurons and oligodendrocytes, α-Synuclein expression in each cell type may be upregulated. Neuronal α-Synuclein secretion and oligodendrocyte α-Synuclein uptake increase due to alterations in membrane interactions and endocytosis pathways. In addition, TPPP/p25α localizes to the oligodendrocyte soma resulting in cellular swelling and reduced autophagy-lysosomal fusion. These conditions enable the formation of Multiple system atrophy (MSA) specific strains within oligodendrocyte cytosol, with the coalescence of strains leading to the formation of glial cytoplasmic inclusions. Altered Oligodendrocyte function is reflected by a reduction in neurotrophic support and the demyelination of neurons. The secretion of MSA α-Synuclein species results in the formation of neuronal cytoplasmic inclusions. Oligodendrocyte precursor cells may also take up α-Synuclein aggregates via altered endocytosis pathways, eventually giving rise to dysfunctional mature oligodendrocytes with a higher propensity to form glial cytoplasmic inclusions. Spreading strain pathology results in oligodendrocyte and neuron degeneration giving rise to oxidative stress, neuroinflammation and astrogliosis. These processes culminate into widespread glial cytoplasmic formation, neurodegeneration and MSA onset