Molecular elucidation of brain lipofuscin in aging and Neuronal Ceroid Lipofuscinosis

Lipofuscin is an autofluorescent material that accrues in brain tissues with age and in Neuronal Ceroid Lipofuscinosis (NCL), a neurodegenerative disease with pediatric onset. The distribution, composition, and organellar origin of lipofuscin have remained unclear despite its widespread presence in aged tissues and involvement in neurodegeneration. Here, we elucidate lipofuscin composition and report the spatiotemporal dynamics of lipofuscin accumulation in aging and NCL on a neuroanatomical atlas. Multimodal mass spectrometry, ultrastructural analyses, and assays of metabolic flux identify a primary role of the lysosomal-mitochondrial axis in lipofuscin formation. Dissection of implicated molecular pathways reveals protein S-acylation and lipid homeostasis as central processes involved in aging and NCL.