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• Generated '2-hit-DA' mice overexpressing ASYN in TH neurons and underexpressing Nurr1. • '2-hit-DA' mice had reduced dopamine, increased metabolic rate and hypoactivity. • Their prolonged hyperactivity in a novel environment indicated impaired habituation. • ASYN-overexpression-in TH neurons leads to age-dependent Nurr1 downregulation in the SN. • ASYN and Nurr1 synergistically alter DAT expression levels and function. Increased expression of alpha-synuclein (ASYN) and decreased expression of Nurr1 are associated with Parkinson's disease (PD) pathogenesis. These two proteins interact functionally and ASYN overexpression suppresses Nurr1 levels. ASYN pan-neuronal overexpression coupled with Nurr1 hemizygosity followed by Nurr1 repression in aging mice results in the manifestation of a typical PD-related phenotype and pathology. Here we investigated in mice the effects of C-terminally truncated ASYN(120) overexpression in dopaminergic (DA-ergic) neurons compounded with Nurr1 hemizygosity ('2-hit-DA'). We report that '2-hit-DA' animals did not manifest a characteristic PD-related phenotype, despite further substantia nigra ASYN-overexpression-dependent and age dependent Nurr1 protein downregulation. However, they displayed increased energy expenditure, reduced striatal dopamine (DA) and prolonged hyperactivity to a novel environment indicating impaired habituation. This DA-ergic dysfunction was observed in young adult '2-hit-DA' mice, persisted throughout life and it was associated with ASYN and Nurr1 synergistic alterations of DAT levels and function. Our experiments indicate that the expression levels of ASYN and Nurr1 are critical in the dysregulation of the nigrostriatal DA system and may be involved in neuropsychiatric aspects of PD. [ABSTRACT FROM AUTHOR]