Alpha-Synuclein Contribution to Neuronal and Glial Damage in Parkinson's Disease

Parkinson's disease (PD) is a complex neurodegenerative disease characterized by the progressive loss of dopaminergic neurons in the substantia nigra and the widespread accumulation of alpha-synuclein (alpha Syn) protein aggregates. alpha Syn aggregation disrupts critical cellular processes, including synaptic function, mitochondrial integrity, and proteostasis, which culminate in neuronal cell death. Importantly, alpha Syn pathology extends beyond neurons-it also encompasses spreading throughout the neuronal environment and internalization by microglia and astrocytes. Once internalized, glia can act as neuroprotective scavengers, which limit the spread of alpha Syn. However, they can also become reactive, thereby contributing to neuroinflammation and the progression of PD. Recent advances in alpha Syn research have enabled the molecular diagnosis of PD and accelerated the development of targeted therapies. Nevertheless, despite more than two decades of research, the cellular function, aggregation mechanisms, and induction of cellular damage by alpha Syn remain incompletely understood. Unraveling the interplay between alpha Syn, neurons, and glia may provide insights into disease initiation and progression, which may bring us closer to exploring new effective therapeutic strategies. Herein, we provide an overview of recent studies emphasizing the multifaceted nature of alpha Syn and its impact on both neuron and glial cell damage.