The most distinctive clinical characteristic of this family was an age of onset in the mid 20 s. Neuropathological examination of the proband also disclosed unusual features, in particular generalized LB pathology and neurofibrillary tangles that colocalized in most of the affected neurons. No amyloid deposits were detected in any brain region. The unusual neuropathological feature in this family together with the observation that coexistence of a-syn and tau pathologies is common in sporadic DLB led us to hypothesize a possible pathological synergistic GDC-0941 citations effect between tau and a-syn. In order to test this hypothesis, in the present article we investigated the effects of tau in various neuronal cell models of a-syn aggregation. We found that tau colocalized with a-syn aggregates in a human cell line and primary neuronal cultures. In addition, overexpression of tau increased the number of a-syn aggregates, the levels of high molecular weight species of a-syn, and enhanced a-syn toxicity. In this study, we showed that tau colocalized and interacted with a-syn aggregates in H4 cells and primary neuronal cultures. This interaction is associated with more a-syn aggregates, HMW species and enhanced toxicity. Thus our results support the notion that tau is not simply a bystander, but rather enhances the pathological aggregation of a-syn. a-syn is a presynaptic protein localized mainly in axon terminals that plays a role in synaptic function. Tau is a microtubule-associated protein localized along the axon that stabilizes microtubules and is involved in cellular trafficking and axonal transport. Both are highly expressed in the CNS, are synthesized as native unfolded proteins and have the propensity to form pathological insoluble intracellular aggregates in the CNS in different neurodegenerative diseases. Few studies have investigated the interaction between these two proteins. Initial studies identified soluble tau as a ligand for a-syn by affinity chromatography and direct binding studies. a-syn has also been shown to stimulate tau phosphorylation at different serine residues in different cellular and animal models. This functional link could be relevant for many neurodegenerative diseases in which a-syn and tau co-aggregate, since an increase in hyperphosphorylated tau is one of the key features in the brains of all tauopathies and has been shown to reduce binding of tau to microtubules. Other studies have also suggested a pathological synergistic effect between a-syn and tau. a-syn can aggregate in vitro, and this is greatly enhanced by co-incubation with tau in a concentration-dependent manner. Interestingly, the effects were specific for tau because coincubation with Ab did not enhance a-syn polymerization. More recently, data obtained from a novel cellular model demonstrated that few amounts of fibrillized a-syn seeds are able to induce intracellular massive tau aggregation. These tau aggregates were hyperphosphorylated and occupied almost all the soma, sharing similar characteristics with neurofibrillary tangles. These data support the idea that cross-seeding of pathologic proteins can occur in some neurodegenerative diseases.