Highlights •HSPA8 knock-down induces HSPA1A overexpression.•HSPA8 and HSPA1A knock-down increases tau, SOD1 and α-synuclein protein levels.•HSPA8 knock-down or macro-autophagy inhibition increase high- and low-molecular weight forms of α-synuclein.•HSPA8 knock-down dysregulates α-synuclein gene transcription. Display omitted Heat shock protein 70 family was demonstrated to play a critical role in protein homeostasis, a process profoundly impaired in neurodegenerative disorders. Neurodegenerative diseases are characterized by the accumulation of different kind of proteins and the formation of insoluble aggregates which are toxic for neurons. To explore the role of heat shock protein family 70 (in particular HSPA8 and HSPA1A) in the accumulation of proteins implied in neurodegeneration pathogenesis, in this study we verified in human SH-SY5Y neuroblastoma cells how HSPA8 or HSPA1A knock-down can affect protein levels of tau, superoxide dismutase 1 and α-synuclein. We found HSPA8 and HSPA1A reduction caused an increase of tau, superoxide dismutase 1 and α-synuclein protein levels. We also noticed HSPA8 knock-down increased α-synuclein oligomeric forms and mRNA expression. Our results suggest HSPA8 can play an important role in the homeostasis of tau, superoxide dismutase 1 and α-synuclein and in the balance between α-synuclein oligomeric and monomeric forms.