Parkinson’s disease (PD) is a chronic neurodegenerative disorder mainly characterized by progressive loss of dopaminergic neurons in the substantia nigra pars compacta (SNpc). Albeit diverse efforts have been carried out to halt the progression of PD, none of them have been fully satisfactory. The possible implication of transcription factor EB (TFEB) as a therapeutic target in PD has gained momentum since it was discovered that TFEB controls lysosomal biogenesis and autophagy and that its activation might counteract lysosomal impairment and protein aggregation, which have long been described in neurodegenerative diseases, including PD. However, the majority of putative direct targets of TFEB described to date is linked to a range of biological processes that are not related to the autophagy-lysosomal system. Therefore, to deepen our knowledge on TFEB function in neurons may be crucial to develop a potential therapeutic strategy for PD and other related neurological disorders. In this thesis, we assessed the effect of overexpressing TFEB by means of an adeno-associated viral vector in mouse substantia nigra dopaminergic neurons and studied several molecular processes activated upon TFEB overexpression that may offer potential benefits in the context of PD. In this line, we demonstrated that TFEB overexpression drove a previously unknown bona fide neurotrophic effect accompanied by an enhanced dopaminergic function, activation of pro-survival signaling pathways and mitochondrial changes that altogether may contribute to render neurons less prone to cell death. To delve further into this concept, we studied the therapeutic potential of TFEB in a parkinsonian context, that induced by the neurotoxin MPTP. In this regard, we showed that TFEB overexpression was indeed able to block MPTP-induced neurodegeneration both at the cell body level as well as striatal dopaminergic terminals and restored neuronal activity/function and phenotype in the MPTP mouse model of PD. Moreover, TFEB overexpression also counteracted the deleterious events like lysosomal depletion and mitochondria-mediated cell death that are linked to MPTP neurotoxicity and PD. Besides, we unraveled that activating the autophagy-lysosomal pathway by knocking down the master repressor of autophagy ZKSCAN3 did not prevent MPTP-induced neurodegeneration or atrophy. Altogether, our results uncover new mechanisms decisive for the neuroprotective effect elicited by TFEB and highlight increasing TFEB activity as a therapeutic approach to fight neuronal death and restore neuronal function in PD and other neurodegenerative diseases.