Mitochondrial parkinsonian neurotoxin 1-methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine (MPTP) reproduces several PD-linked cellular alterations, such as inhibition of mitochondrial complex I, increased production of reactive oxygen species (ROS), oxidative damage to lipids, DNA and proteins (including α-synuclein), activation of mitochondriadependent apoptotic pathways and dopaminergic cell death in the substantia nigra pars compacta (SNpc), the most affected area in PD brains. We found that MPTP induces a time-dependent accumulation of LC3-II-positive AP in the ventral midbrain of intoxicated mice, which precedes dopaminergic cell death in this model. Remarkably, MPTP-induced AP accumulation is preceded by a marked decrease in the amount of lysosomes within affected dopaminergic neurons, as indicated by reduced levels of lysosomal structural protein LAMP-1 and a severe reduction in the amount of retrieved lysosomes in purification experiments. Lysosomal depletion following MPTP intoxication cannot be attributed to a reduced number of dopaminergic cells in these animals, as it occurs prior to dopaminergic cell death, nor to a transcriptional downregulation of lysosomal markers. Relevant to PD, decreased lysosomal markers and accumulation of LC3-II also occurred in post-mortem nigral brain tissue from PD patients. In these samples, LC3 was identified as a major component of Lewy bodies, raising the possibility that Lewy bodies, of which the origin and significance are currently unknown, may derive from undegraded AP.