α-Synuclein is a presynaptic neuronal protein linked genetically and neuropathologically to Parkinson's disease (PD). Its aberrant soluble oligomeric conformations, termed protofibrils, are believed to mediate disruption of cellular homeostasis and neuronal death through effects on various intracellular targets, including synaptic function. Secreted α-synuclein may also exert deleterious effects on neighboring cells, potentially contributing to disease propagation. While the extent of α-synuclein's involvement in all cases of PD is unclear, targeting its toxic functions when dysregulated may lead to novel therapeutic strategies for PD and other synucleinopathies. The first genetic link between PD and α-synuclein was discovered in 1997, identifying a mutation in the SNCA gene encoding α-synuclein. This discovery opened the door to extensive genetic studies, culminating in genome-wide association studies (GWAS) that have confirmed the robust association of SNCA with sporadic PD. Abnormal α-synuclein pathology is also abundant in neuropathological specimens from PD patients and other neurodegenerative conditions, collectively termed "synucleinopathies." α-Synuclein is robustly expressed within Lewy bodies (LBs) and is present in neuritic processes, widespread in various brain regions, and present in multiple synucleinopathies. The distribution of pathology at the cellular and regional level varies among diseases. α-Synuclein is a member of the synuclein family, with a unique NAC region that confers β-sheet potential. It is involved in synaptic transmission and may act as a chaperone-like protein in the assembly of the SNARE complex. Cellular and animal models of α-synuclein overexpression have been developed to study its pathological effects. α-Synuclein aggregation is a key pathogenic feature, with soluble oligomeric species being particularly neurotoxic. Posttranslational modifications, such as phosphorylation and oxidation, can influence α-synuclein's aggregation and toxicity. α-Synuclein may also interact with various proteins and lipids, affecting synaptic function and cytoskeletal dynamics. The gain-of-function hypothesis suggests that enhanced α-synuclein levels are causative in PD pathogenesis, supported by familial SNCA multiplication cases and increased α-synuclein levels in aging substantia nigra. However, the exact mechanism of toxicity remains unclear, and the role of total α-synuclein levels versus specific forms is debated. Strategies to lower α-synuclein levels or enhance its degradation may be promising therapeutic approaches.α-Synuclein is a presynaptic neuronal protein linked genetically and neuropathologically to Parkinson's disease (PD). Its aberrant soluble oligomeric conformations, termed protofibrils, are believed to mediate disruption of cellular homeostasis and neuronal death through effects on various intracellular targets, including synaptic function. Secreted α-synuclein may also exert deleterious effects on neighboring cells, potentially contributing to disease propagation. While the extent of α-synuclein's involvement in all cases of PD is unclear, targeting its toxic functions when dysregulated may lead to novel therapeutic strategies for PD and other synucleinopathies. The first genetic link between PD and α-synuclein was discovered in 1997, identifying a mutation in the SNCA gene encoding α-synuclein. This discovery opened the door to extensive genetic studies, culminating in genome-wide association studies (GWAS) that have confirmed the robust association of SNCA with sporadic PD. Abnormal α-synuclein pathology is also abundant in neuropathological specimens from PD patients and other neurodegenerative conditions, collectively termed "synucleinopathies." α-Synuclein is robustly expressed within Lewy bodies (LBs) and is present in neuritic processes, widespread in various brain regions, and present in multiple synucleinopathies. The distribution of pathology at the cellular and regional level varies among diseases. α-Synuclein is a member of the synuclein family, with a unique NAC region that confers β-sheet potential. It is involved in synaptic transmission and may act as a chaperone-like protein in the assembly of the SNARE complex. Cellular and animal models of α-synuclein overexpression have been developed to study its pathological effects. α-Synuclein aggregation is a key pathogenic feature, with soluble oligomeric species being particularly neurotoxic. Posttranslational modifications, such as phosphorylation and oxidation, can influence α-synuclein's aggregation and toxicity. α-Synuclein may also interact with various proteins and lipids, affecting synaptic function and cytoskeletal dynamics. The gain-of-function hypothesis suggests that enhanced α-synuclein levels are causative in PD pathogenesis, supported by familial SNCA multiplication cases and increased α-synuclein levels in aging substantia nigra. However, the exact mechanism of toxicity remains unclear, and the role of total α-synuclein levels versus specific forms is debated. Strategies to lower α-synuclein levels or enhance its degradation may be promising therapeutic approaches.