Neurotoxic conversion of β-synuclein: a novel approach to generate a transgenic mouse model of synucleinopathies?

Many groups have generated α-synuclein (α-syn) transgenic (tg) mice as a rodent model for human synucleinopathies, including Parkinson’s disease and dementia with Lewy bodies (DLB). Indeed, some of the lines displayed limited evidence of neurodegeneration, such as α-syn deposits, compromised function of dopaminergic neurons, fibrillization of α-syn, and astrogliosis. However, none of them fully replicate the pathological features of synucleinopathies. To better understand the pathogenesis of the synucleinopathies and to develop new therapeutic strategies, improvement of the current version of α-syn tg mice may be required. We predict that β-synuclein (β-syn), the homologue of α-syn, might be a key molecule for this purpose. Although β-syn is a neuroprotective molecule counteracting the α-syn pathology in tg mice, it was previously shown that both β-syn and γ-synuclein were associated with axonal pathology in the hippocampus of sporadic cases of Parkinson’s disease and DLB. Furthermore, two missense mutations (P123H and V70M) of β-syn were recently identified in DLB. These mutants of β-syn were prone to aggregate in vitro and overexpression of these mutant β-syn proteins in neuroblastoma cells resulted in enhanced lysosomal pathology. Taken together, these results suggest that a toxic gain of function of β-syn might be involved in the pathogenesis of synucleinopathies. In this context, it is of considerable interest to determine if mutant β-syn-overexpressing tg mice could exhibit neuropathological features distinct from those in conventional α-syn tg mice. Furthermore, it is expected that a bigenic mouse model for mutant β-syn/α-syn might be characterized by a more accelerated phenotype of synucleinopathies.