β-Synuclein Inhibits α-Synuclein Aggregation A Possible Role as an Anti-Parkinsonian Factor

within the ␣-synuclein molecule, which self-aggregates to 2 Department of Pathology form amyloid and is an efficient seed for formation of A␤ subsequently found to belong to a larger family of molecules , including ␤-synuclein (or phosphoneuroprotein 14) (Jakes et al. We characterized ␤-synuclein, the non-amyloidogenic molecule is a natively unfolded protein (Weinreb et al., homolog of ␣-synuclein, as an inhibitor of aggregation 1996) that is capable of self-aggregating to form both of ␣-synuclein, a molecule implicated in Parkinson's dis-oligomers and fibrillar polymers with amyloid-like char-ease. For this, doubly transgenic mice expressing human acteristics (Hashimoto et al., 1998). Polymerization (h) ␣-and ␤-synuclein were generated. In doubly trans-could occur in several stages including formation of genic mice, ␤-synuclein ameliorated motor deficits, neu-protofibrils, nucleation (Wood et al., 1999), and fibril for-rodegenerative alterations, and neuronal ␣-synuclein mation (Hashimoto et al., 1998; Serpell et al., 2000). accumulation seen in h␣-synuclein transgenic mice. Conditions promoting this aggregation include: (1) muta-Similarly, cell lines transfected with ␤-synuclein were tions associated with familial parkinsonism (Conway et resistant to ␣-synuclein accumulation. h␣-synuclein al., 1998; Narhi et al., 1999), (2) oxidative stress mediated was coimmunoprecipitated with h␤-synuclein in the by iron, cytochrome c, or copper(II) (Hashimoto et al., transfected cell lines. Our results raise the possibility Souza et al., 2000), (3) binding to lipid membrane vesi-that ␤-synuclein might be a natural negative regulator cles (Jo et al., 2000; Perrin et al., 2000), and (4) interac-of ␣-synuclein aggregation and that a similar class of tions with amyloidogenic molecules such as NAC and endogenous factors might regulate the aggregation Such an anti-amyloidogenic property of ␤-synuclein In view of evidence suggesting that ␣-synuclein fibrils might also provide a novel strategy for the treatment may initiate neurodegeneration in vivo, inhibition of of neurodegenerative disorders. ␣-synuclein aggregation may represent a feasible therapeutic strategy in LBD and related disorders. While Introduction some factors promote ␣-synuclein aggregation, others might block amyloidogenesis and aggregation (Hashi-Abnormal folding and aggregation of proteins in the moto and Masliah, 1999). Interactions among the sy-central nervous system (CNS) has been extensively ex-nucleins could play a role in this process, because plored as one of the central mechanisms leading to neu-␤-and ␥-synuclein do not seed ␣-synuclein aggregation rodegeneration in disorders such as Alzheimer's disease (Biere et al., 2000) and in LBD the ratio of ␤-to (AD), Lewy body disease (LBD), Huntington's disease ␣-synuclein is altered (Rockenstein et al., 2001), sug-(HD), and Creutzfeldt-Jakob disease (CJD) …