Is Multiple System Atrophy a New Prion Disorder?

In the last years, several experimental studies have shown that abnormal alpha-synuclein (a-Syn) aggregates might be responsible for progression of pathology in Parkinson’s disease (PD) and other synucleinopathies, such as multiple system atrophy (MSA). MSA is a sporadic disease associated with parkinsonism, cerebellar ataxia, as well as autonomic failure. In contrast with PD, where a-Syn mainly accumulates in neurons, MSA brains are mainly characterized by a-Syn-rich oligodendroglial cytoplasmic inclusions (GCIs). Supporting the possible prion-like property of aSyn, Prusiner and colleagues have now confirmed and extended previous results from their group by showing that intracerebral (IC) inoculation with homogenates from MSA patients in TgM83 mice transmits neurodegeneration accompanied by a-Syn accumulation and deposition in mouse brains. This transgenic mouse heterozygous for the human a-Syn (A53T) mutant form does not develop sporadic a-Syn pathology or neurodegeneration in normal conditions. They also show that this prion-like property of a-Syn persists postinoculation, because injections in healthy TgM83 with brain homogenates from the first inoculated TgM83 mice also induced neurodegeneration and a-Syn pathology. Moreover, these homogenates not only remained pathogenic, but also accelerated the pathology. Using an in vitro model based on a cell line that overexpresses the same mutant a-Syn but fused to green fluorescent protein, they directly visualized induction of endogenous a-Syn aggregates in cells. Interestingly, they failed to observe the same effect either in the mouse model or in vitro when homogenates from PD patients were used. Based on this, and together with the fact that the location of a-Syn deposits differs in PD and MSA, they propose that both diseases are caused by different strains of a-Syn prions. Despite the remarkable induction of a-Syn-linked neurodegeneration by MSA homogenates observed by Prusiner and colleagues in TgM83 mice, it must be highlighted that this is a mouse model of familiar PD and not of MSA. As mentioned above, MSA is a sporadic disease and the A53T mutation is not present in MSA patients. Moreover, the researchers failed to induce any effects in wild-type (WT) animals after IC inoculation with MSA homogenates, suggesting that the presence of A53T mutation is essential for the pathological/toxic effect, thus differing from the prion protein responsible for Creutzfeldt-Jakob disease and Kuru, which is capable to induce the pathology in WT animals. Based on this observation, the possible existence of different a-Syn prion strains for PD and MSA proposed by the researchers seems controversial. It is clear that MSA and PD homogenates have different effects in the TgM83 mice model and in the cell line, and Peelaerts and colleagues have shown that IC injection with distinct synthetic strains of recombinant a-Syn (based on different a-Syn assemblies and their structural characteristics) induces diverse pathological manifestations in vivo. However, the fact that Prusiner and colleagues have only observed the effect of MSA homogenates in the presence of A53T mutation, together with the absence of GCIs and other pathologycal hallmarks of MSA in the inoculated mice, suggests that these findings might not be relevant for human pathology. The use of more-specific MSA models in future studies could be of interest to support the observations of Prusiner and colleagues.