Is multiple system atrophy an infectious disease?
Prusiner et al, recently published a series of articles8 in which they assessed whether α‐synuclein aggregates may act as prions and whether MSA is a prion disease. In Prusiner's definition, prion is a small proteinaceous infectious particle which is resistant to inactivation by most procedures that modify nucleic acids.12 Infectivity is broadly accepted as a core feature of prions and is therefore required to define prion diseases. For this reason, Prusiner's hypothesis has several theoretical and practical implications.
Both evidence of self‐templating propagation in cellular cultures and infectivity in animal models and in humans are required to define MSA as a prion disease. Furthermore, evidence that exogenous mutant α‐synucleins may produce α‐synuclein pathology when transmitted to healthy subjects is required to assess α‐synuclein aggregates' infectivity. There is no documented infectious spread of MSA and related synucleinopathies from human to human.
However, there is evidence of misfolded α‐synuclein self‐propagating in neural cell cultures,9 and embryonic stem cells injected into the striatum of patients with PD showed evidence of α‐synuclein associated pathology in the grafted cells, suggesting a host‐to‐graft self‐propagation of the misfolded proteins.14 A cell‐to‐cell self‐spreading pattern resembles prion spreading and has led to the concept of prion‐like propagation for α‐synuclein, β‐amyloid, and tau.16 Self‐propagation of α‐synuclein oligomers in vitro is not sufficient to define them as prions, because the evidence of infectivity cannot be assessed at a cellular level.
Converging data suggest that misfolded α‐synuclein17 and β‐amyloid18 are able to propagate in a connectome‐dependent manner within the central nervous system (CNS) after intracerebral inoculation in nontransgenic mice.17 Furthermore, intracerebral inoculation of misfolded α‐synuclein seems to anticipate and accelerate neurodegeneration in several transgenic mice models carrying mutations that predispose animals to the development of α‐synuclein‐related pathology.19 These latter observations show “seeding” activity rather than infectivity of α‐synuclein.
Recently, Prusiner et al reported in a series of articles that both intracerebral11 and peripheral21 inoculation of brain homogenates derived from MSA patients, but not from PD patients, were able to produce α‐synuclein pathology in TgM83+/−, but not in TgM83−/− wild‐type mice. The researchers hypothesize that different α‐synuclein strains may show different infectivity and may determine different α‐synucleinopathies' phenotypes.11 Furthermore, the same group showed that α‐synuclein aggregates (that the researchers call “prions”) exhibit stability and resistance to denaturation and can be transmitted by means of surgical devices in TgM83+/− mice, raising the hypothesis of a risk for iatrogenic transmission of the disease (indirect, vehicle‐borne transmission).21
It should be noted that Prusiner et al tested their hypothesis using a TgM83+/− mouse model.23 TgM83+/+ homozygous mice express mutant A53T α‐synuclein and spontaneously develop α‐synuclein pathology whereas TgM83+/− hemizygous mice do so to a lesser degree and at much older ages. A53T α‐synuclein mutation has been primarily identified in PD patients, but it has never been documented in patients with MSA. TgM83 mice cannot be therefore considered a valid animal model for MSA.