<p>A significant advancement in neurodegenerative research was the discovery that <i>α</i>-synuclein (<i>α</i>-Syn/SNCA) plays a part in the pathophysiology of Parkinson's disease (PD). Decades later, the protein's significant impacts on various brain disorders are still being extensively explored. In disease conditions, <i>α</i>-Syn misfolds and forms abnormal aggregates that accumulate in neurons, thus triggering various organellar dysfunctions and ultimately neurodegeneration. These misfolded forms are highly heterogeneous and vary significantly among different synucleinopathies, such as PD, Multiple System Atrophy, or Dementia with Lewy bodies. Though initially believed to be exclusively localized in the brain, numerous pieces of evidence suggest that <i>α</i>-Syn functions transcend the central nervous system, with roles in peripheral functions, such as modulation of immune responses, hematopoiesis, and gastrointestinal regulation. Here, we aim to provide a detailed compilation of cellular functions and pathological phenotypes that are altered upon attenuation of <i>α</i>-Syn function in vitro and in vivo and explore the effects of <i>SNCA</i> gene silencing in healthy and disease states using cellular and animal models.</p> Graphical Abstract <p>Physiological and pathological consequences of α-Syn’s ablation.α-Syn’s ablation induces cellular and physiological changes, including synaptic abnormalities, altered leukocyte development, inflammation, neurodegeneration, and lipid dysfunction</p>