An important turning point in understanding Parkinson's disease was the realization that altered function of α-synuclein (αS) is central to disease pathogenesis. β-synuclein (βS), the homolog of αS, received limited attention initially, but further work indicated that βS may be involved in the pathogenesis of Parkinson's disease and other α-synucleinopathies. βS can protect against neurodegeneration caused by αS, and mutations in the βS gene have been linked to dementia with Lewy bodies. When we created transgenic mice expressing the P123H βS mutation, we observed neurodegeneration characterized by axonal pathology and gliosis. Furthermore, P123H-βS transgenic mice exhibited memory dysfunction, suggesting that alteration of neuroprotective βS function contributes to non-motor symptoms. Similar to other amyloidogenic proteins, βS may yield neurodegeneration through both loss-of-function and gain-of-function mechanisms. Such diverse modes of action need to be carefully considered, as βS is emerging as an attractive candidate for therapy development.