The necessity of understanding causes of neurodegenerative diseases and developing potentialtreatments is increasing as life expectancy is extending. Neuronal ceroid lipofuscinoses (NCLs; alsoknown as Batten disease) comprise a group of 14 monogenic neurodegenerative diseases withlysosomal pathology (CLN1-14). NCLs are typically due to recessive mutations in genes that mediatelysosomal function or ER-lysosomal trafficking with one atypical exception: the dominantly inherited NCLCLN4 which is caused by mutations in the synaptic vesicle (SV) protein CSP. Normally CSP is criticalto maintain synaptic function and prevent activity-dependent neurodegeneration. It also mediates theclearance of aggregating proteins like TDP-43 or -synuclein by unconventional secretion pathways. Little is known about CLN4 disease etiology besides biochemical evidence that CLN4-causingmutations induce the formation of ubiquitinated CSP oligomers/aggregates. Whether and how theoligomeric or monomeric protein causes lysosomal failure neurodegeneration and premature deathremains enigmatic. We have established the first animal models of CLN4 by expressing disease-causinghuman CSP (hCSP) or fly CSP (dCSP) in Drosophila neurons. Both models recapitulate thebiochemical pathology of CLN4 post-mortem brains. Further analysis revealed a novel link betweenCLN4 mutant CSP and prelysosomal failure. Unexpectedly we also found that the dominant CLN4alleles act as hypermorphic gain of function mutations inducing the oligomerization of CSP prelysosomalfailure neurodegeneration and lethality. We suggest that hypermorphic CLN4 mutations increase the affinity for some or one of CSPs proteininteraction causing disease. Next to an exaggerated dimerization of CSP leading to oligomerizationCLN4 mutations increase interactions of CSP with the synaptically localized palmitoyl-transferase Hip14that could lead to prelysosomal failure. Finally increased interactions of CSP with Hsc70 on endosomesdestined to form multivesicular bodies may interfere with their processing sorting and/or trafficking. Wepropose to test these possibilities by genetic approaches to better understand both the mechanismsunderlying CSPs normal neuroprotective role and the mechanisms underlying the hypermorphic CLN4mutations causing protein aggregation lysosomal failure neurodegeneration and premature death. Uncovering mechanisms underlying CLN4 may inform the future development of therapeuticinterventions. In addition a better understanding of CSPs neuroprotective role is important for variousother neurodegenerative diseases that may be attenuated by CSPs clearance of misfolded proteins.