Abstract: Synucleinopathies are a group of progressive neurodegenerative disorders characterized by the accumulation of α-synuclein (α-Syn) aggregates in Lewy bodies (LBs) and Lewy neurites (LNs) in Parkinson’s disease (PD) and dementia with Lewy bodies (DLB), and in glial cytoplasmic inclusions in multiple system atrophy (MSA). α-Syn is a 140 amino acid intrinsically disordered protein, which tends to self-aggregate and form fibrils in these neuropathological hallmark inclusions. Several lines of evidence suggest that misfolding and aggregation of α-Syn is a critical step leading to neuronal dysfunction and death. Additionally, propagation of α-Syn aggregates across neurons to synaptically connected brain regions correlates with the progressive nature of synucleinopathies and the emergence of additional clinical manifestations as the disease advances over time. Currently, there is no cure for these disorders. Available treatments for PD improve the motor symptoms but do not halt the underlying neurodegeneration. Thus, from the therapeutic perspective, identifying factors that initiate or promote misfolding of α-Syn is critical to developing strategies that reduce or prevent the formation of pathologic aggregates and thereby slow disease progression. In addition to well established genetic factors such as disease linked point mutations and SNCA gene locus multiplication leading to elevated levels of α-Syn, a number of exogenous and endogenous factors have been identified that can contribute to the formation of these aggregates including oxidative stress, exposure to neurotoxins, hyper-phosphorylation of α-Syn, and protein cross-linking. Several lines of evidence have attributed the latter to the activity of transglutaminase 2 (TG2).