ALPHA-synuclein – Can it form prions?

Abstract

α-Synuclein (αS), a natively unfolded protein containing 140 amino acids, can be the cause of Parkinson’s disease (PD), dementia with Lewy bodies (DLB) and multiple system atrophy (MSA). To date, several missense mutations in the αS gene (SNCA), as well as occurrence of gene duplication and triplication, have been identified in familial forms of PD and DLB. Furthermore, αS is the major component of Lewy bodies and Lewy neurites in PD and DLB, and glial cytoplasmic inclusions in MSA. The distribution and spreading of these pathologies are closely correlated with disease symptoms and progression, suggesting that propagation of pathological αS is the cause of neurodegeneration in these diseases. Recent studies have demonstrated that the abnormal forms of αS (synthetic αS fibrils prepared from recombinant protein or pathological αS prepared from brains of patients) have prion-like properties which can convert normal αS to an abnormal form in vitro and in vivo. Intracerebral injection of these pathological αS into transgenic or wild-type mouse brains induced prion-like propagation of abnormal αS pathology. In addition, injection of the αS fibrils into striatum of wild-type marmoset brains also resulted in spreading of αS pathologies, including robust Lewy body-like inclusions in TH-positive neurons and a significant decrease in the numbers, suggesting the retrograde spreading of abnormal αS and the toxicities. These results strongly suggest that cell to cell transmission of pathological αS play a key role in the progression of α-synucleinopathies. There is an argument whether we should call these αS aggregates prions or prion-like proteins. Several reports have shown that peripheral inoculation of synthetic αS fibrils or MSA brain homogenates into transgenic mice (TgM83 mice) can induce αS pathologies and lethal CNS disorders. On the other hand, αS pathology was not induced in WT mice by inoculation into hindlimb muscle or oral inoculation of even large amounts of synthetic αS fibrils. Further studies are needed to clarify this issue.