Alpha-synuclein (α-syn) has long been identified as the etiologic agent of multiple neurodegenerative diseases, the most common and well-known of which are Parkinson’s disease (PD) and Lewy body dementia (LBD). While it is known that the pathophysiology of these synucleinopathies involves aggregation of improperly-folded α-syn, the mechanisms leading to its accumulation have not been fully identified. However, multiple pathways have been proposed, any or all of which may contribute to synucleinopathies. The role of α-syn in normal homeostasis and in other organ systems, especially the hematopoietic system, has been reported recently. Research within the last decade has shown that α-syn plays many vital and conserved roles in the cell biology of various organ systems, such as packaging of cell products, exocytosis, membrane stabilization, and more. This protein has been recognized as an essential factor in normal hematopoietic and immune systems function, and its deficiency leads to an abnormal phenotype, in hematopoietic and immune cell lineages. Similar phenotypes in synucleinopathies not only emphasize the conserved nature of the synuclein family but suggest a bimodal pathophysiology in which aggregated α-syn leads to cellular toxicity while causing derangement of systems that require it. Research into specific molecular mechanisms and potential treatments may provide further understanding of neurodegenerative diseases as well as lead to novel therapies. However, elucidation of the systemic roles of α-syn in addition to its toxicity in excess is essential to prevent treatment-induced deprivation, which paradoxically harms the patient. Here, we address recent advances in systemic synucleinopathies and putative interconnectedness of these compartments. While previous studies and reviews have focused on the mechanisms of α-syn synthesis, transport, and aggregation within systems, this review focuses on the potential inter-systemic nature of synucleinopathies and their possible synergistic origins.