Fragmentation of the Golgi ribbon is a common feature of many neurodegenerative diseases but little is known about the causes of this alteration. In Parkinson's disease, it is believed to be the consequence of an ER-Golgi transport imbalance and/or of cytoskeleton alterations. In the present study, we analyze the mechanisms involved in Golgi fragmentation in differentiated PC12 cells treated with 6-hydroxydopamine or methamphetamine as cellular models of Parkinson's disease. Our data demonstrate that Golgi fragmentation precedes and might trigger the aggregation of α-synuclein and the formation of inclusions, alterations in anterograde and retrograde transport between the endoplasmic reticulum and Golgi complex, and cytoskeleton damage. In contrast, fragmentation is directly related with alterations in the levels of Rab1, 2 and 8 and the SNARE protein syntaxin 5. Thus, overexpression of Rab1 and 8 and depletion of Rab2 and syntaxin 5 rescue the Golgi morphology. In conclusion, the homeostasis of a limited number of Rab and SNARE proteins is important for understanding the cytopathology of Parkinson's disease.