Combination therapies: The next logical Step for the treatment of synucleinopathies?

Currently there are no disease-modifying alternatives for the treatment of most neurodegenerative disorders. The available therapies for diseases such as Parkinson's disease (PD), PD dementia (PDD), dementia with Lewy bodies (DLB), and multiple system atrophy (MSA), in which the protein alpha-synuclein (α-Syn) accumulates within neurons and glial cells with toxic consequences, are focused on managing the disease symptoms. However, using strategic drug combinations and/or multi-target drugs might increase the treatment efficiency when compared with monotherapies. Synucleinopathies are complex disorders that progress through several stages, and toxic α-Syn aggregates exhibit prion-like behavior spreading from cell to cell. Therefore, it follows that these neurodegenerative disorders might require equally complex therapeutic approaches to obtain significant and long-lasting results. Hypothetically, therapies aimed at reducing α-Syn accumulation and cell-to-cell transfer, such as immunotherapy against α-Syn, could be combined with agents that reduce neuroinflammation with potential synergistic outcomes. Here we review the current evidence supporting this type of approach, suggesting that such rational therapy combinations, together with the use of multi-target drugs, may hold promise as the next logical step for the treatment of synucleinopathies.