α-Synuclein: Multiple System Atrophy Prions

Abstract

Multiple system atrophy (MSA) is a rapidly progressive neurodegenerative disease arising from the misfolding and accumulation of the protein α-synuclein in oligodendrocytes, where it forms glial cytoplasmic inclusions (GCIs). Several years of studying synthetic α-synuclein fibrils has provided critical insight into the ability of α-synuclein to template endogenous protein misfolding, giving rise to fibrillar structures capable of propagating from cell to cell. However, more recent studies with MSA-derived α-synuclein aggregates have shown that they have a similar ability to undergo template-directed propagation, like PrP prions. Almost 20 years after α-synuclein was discovered as the primary component of GCIs, α-synuclein aggregates isolated from MSA patient samples were shown to infect cultured mammalian cells and also to transmit neurological disease to transgenic mice. These findings argue that α-synuclein becomes a prion in MSA patients. In this review, we discuss the in vitro and in vivo data supporting the recent classification of MSA as a prion disease.

Figure 1.

Glial cytoplasmic inclusion (GCI) neuropathology in a multiple system atrophy (MSA) patient sample. GCIs in the basal ganglia from an MSA patient sample were immunostained using the α-synuclein antibody clone 42 (BD Biosciences). (A) Microscopic examination of the patient sample shows dense α-synuclein neuropathology throughout the basal ganglia. (B) Magnification of inset from A shows α-synuclein accumulation into GCIs, indicated by arrows. Scale bar, 100 µm.

Figure 2.

Stable propagation of multiple system atrophy (MSA) prions in cultured cells. HEK293T cells expressing α-synuclein with the A53T mutation fused to yellow fluorescent protein (α-syn140*A53T–YFP cells) were infected with α-synuclein prions isolated from patient MSA14. (A) Two monoclonal cell lines stably propagating the MSA prions were established using fluorescence-activated cell sorting (FACS). Lysate from two clones, MSA14-11 and MSA14-M1, as well as from uninfected α-syn140*A53T–YFP cells, was collected. (B) MSA14-11, MSA14-M1, and α-syn140*A53T–YFP lysates were incubated with naïve α-syn140*A53T–YFP cells at a final protein concentration of 0.1 μg for 3 d. The cells were imaged using the GE IN Cell Analyzer 6000, and the total fluorescence per cell was measured for each condition. MSA14-11 and MSA14-M1 lysate both induced a robust infection in the α-syn140*A53T–YFP cells, compared with lysate from uninfected cells. ***, P < 0.001.