Spinal muscular atrophy (SMA) is a human disease caused by reduced levels of the Survival of Motor Neuron (SMN) protein, leading to progressive loss of motor neurons and muscular paralysis. However, it is still not very clear why these cells are specifically sensitive to SMN levels. Therefore, understanding which proteins may functionally interact with SMN in a neuronal context is a very important issue. PPP4R2, a regulatory subunit of the protein phosphatase 4 (PPP4C), was previously identified as a functional interactor of the SMN complex, but has never been studied in neuronal cells. In this report, we show that PPP4R2 displays a very dynamic intracellular localization in mouse and rat neuronal cell lines and in rat primary hippocampal neurons, strongly correlating with differentiation. More importantly, we found that PPP4R2 loss of function impairs the differentiation of the mouse motor-neuronal cell line NSC-34, an effect that can be counteracted by SMN overexpression. In addition, we show that PPP4R2 may specifically protect NSC-34 cells from DNA damage-induced apoptosis and that it is capable to functionally cooperate with SMN in this activity. Our data indicate that PPP4R2 is a SMN partner that may modulate the differentiation and survival of neuronal cells.