Parkinson’s disease (PD) is the second most common neurodegenerative disorder. The disease is mainly characterized by the progressive loss of dopaminergic neurons in the substantia nigra pars compacta (SNpc) and the abnormal accumulation and aggregation of alpha-synuclein (alpha-syn) in the form of Lewy bodies and Lewy neurites. Even if recent studies allowed for an increased understanding of the role of alpha-syn misfolding and aggregation in PD pathogenesis, many other aspects influence disease onset and progression; among them, evidence suggests neuroinflammation as a key factor of PD cascade. Here, we aim at evaluating the role of Nuclear factor erythroid-derived 2-like 2 (Nrf2), a master regulator of cells homeostasis, as a possible link between neuroinflammation and alpha-syn-induced detrimental effects. Indeed, recent pilot studies found higher activation of Nrf2 pathway (Nrf2PW) in peripheral blood mononuclear cells of PD patients and detected elevated alpha-syn-specific T cells response in PD patients prior to the diagnosis.To study the progression of the alpha-syn induced toxic effects and neuroinflammation, we used the alpha-syn-preformed fibrils (PFF) mouse model, from early to late stages of the disease. A combination of confocal imaging, biochemistry, molecular biology and behavioral assays was used to analyse the alpha-syn-PFF-mediated effects on neurons, focusing on Nrf2PW, for a deeper comprehension of its role in PD cascade. Moreover, we used dimethyl fumarate (DMF), a known Nrf2 activator, as a proof-of-concept of Nrf2 involvement in PD neuropathology and to evaluate the repurposing of DMF as a disease-modifying drug for PD.