Neurodegenerative changes initiated by presynaptic dysfunction

α-Synucleinopathies are a subgroup of neurodegenerative diseases including dementia with Lewy bodies (DLB) and Parkinson’s disease (PD). Pathologically, these disorders can be characterized by the presence of intraneuronal aggregates composed mainly of α-synuclein (αSyn), which are called Lewy bodies and Lewy neurites. Recent report showed that more than 90% of αSyn aggregates are present in the form of very small deposits in presynaptic terminals of the affected neurons in DLB. However, the mechanisms responsible for presynaptic accumulation of abnormal αSyn remain unclear. In this article, we review recent findings on the involvement of presynaptic dysfunction in the initiation of neuronal dysfunctional changes. This review highlights that the presynaptic failure can be a potential trigger of the dying-back neuronal death in neurodegenerative diseases.