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Many neurodegenerative diseases are characterized by abnormal accumulations of insoluble protein aggregates, such as Amyloid beta oligomers in Alzheimers disease and α-synuclein in Parkinsons disease.Brains in these diseases also show accumulation of autophagic vesicles in the neuron, suggesting block of the autophagic process.As lysosomal degradation is involved in all kinds of the autophagy pathway, extensive enhancement of lysosomal function is necessary.However, the involvement of lysosomal membrane proteins in autophagy and their roles in neurodegenerative diseases are not clear.Here we demonstrated that the PD-like neurodegenerative changes induced by rotenone in nigral dopamine neurons and dopaminergic cells were closely linked to a progressive decline in markers of lysosome function.We also found DNA damage-regulated autophagy modulator1 (DRAM1), an essential protein in TP53-dependent autophagy and apoptosis, was involved in this phenomenon.The rotenone-induced damage in dopamine neurons, observed in the MES 23.5 cells as well as in rat model,was reversed by overexpression DRAM1, while inhibition of DRAM1 expression by shRNA aggravated the damage induced by rotenone.Our results showed that DRAM1 afforded neuroprotection via the degradation of α-synuclein.Inhibition of autophagy activation by Bafilomycin or 3-MA blocked DRAM1-induced degradation of α-synuclein.The results provided a mechanistic link between α-synuclein toxicity and impaired DRAM1 function, supported DRAM1 as a key player in autophagy as well as against α-synuclein-induced toxicity, thus identifying DRAM1 as a promising target for therapies aimed at neuroprotection and disease modification in PD.