Abstract: The invention describes methods for treating neurodegenerative diseases by modulating the expression of DENN in neuronal cells. It has been observed that neurodegenerative disease states are characterized by abnormal expression of DENN. The overexpression of DENN induces cell death in neuronal cells. However, reduced expression of DENN also characterizes neural tissue affected by neurodegenerative disease. Also disclosed are methods for treating neurodegenerative diseases by inhibiting the interaction of DENN-MADD (Differentially Expressed in Normal versus Neoplastic/MAPK Activating Death Domain containing)protein, also referred to herein as DENN, with c-Jun N-terminal kinases (JNKs). The invention further describes methods for treating neurodegenerative diseases by inhibiting the interaction of DENN-MADD with the p55 tumor necrosis factor receptor I (TNFRI).