Neurodegenerative diseases (NDs), including dementia, Parkinson's, and motor neuron diseases, represent a significant and growing challenge in global healthcare. These conditions are particularly devastating for patients and their families. Despite extensive research, decisive cures remain elusive. This is largely due to the insufficient understanding of the pathogenic mechanisms underlying NDs. Addressing NDs is crucial due to their severe impact on individuals’ quality of life, the increasing prevalence as populations age, and the substantial healthcare burdens they impose. Improved understanding and innovative treatments are urgently needed to alleviate both personal and societal costs. The CROSS-NEUROD program aimed to elucidate common cellular and molecular pathways in NDs, exploring both autonomous and non-autonomous mechanisms. By leveraging advanced three-dimensional (3D) cell culture systems, our project aimed to uncover shared genetic and molecular mechanisms across different NDs. This approach is pivotal in identifying potential targets for therapeutic intervention. Throughout the project, we identified critical pathways and genes that are consistent across various NDs, with a particular focus on post-translational protein modifications such as sumoylation and prenylation, and specific genes like STMN2. These findings are promising due to their potential translational impact on the development of new treatment strategies for ND patients. The elucidation of these shared mechanisms in human-relevant models establishes a foundation for future therapeutic advancements, potentially leading to effective prevention and treatment options for a spectrum of neurodegenerative conditions.