Neuronal lipofuscinosis caused by Kufs disease/CLN4 DNAJC5 mutations but not by a CSPα/DNAJC5 deficiency.

Kufs disease/CLN4 is an autosomal dominant neurodegenerative disorder caused by unknown mechanisms through Leu(115)Arg and Leu(116)Δ mutations in the DNAJC5 gene that encodes the synaptic vesicle co-chaperone cysteine string protein α (CSPα/DNAJC5). To investigate the disease mechanisms in vivo, we generated three independent mouse lines overexpressing different versions of CSPα/DNAJC5 under the neuron-specific Thy1 promoter: wild-type (WT), Leu(115)Arg, and Leu(116)Δ. Mice expressing mutant Leu(115)Arg CSPα/DNAJC5 are viable but develop motor deficits. As described in patients with Kufs disease, we observed the pathological lipofuscinosis and intracellular structures resembling granular osmiophilic deposits (GRODs) in the mutant but not in the WT transgenic lines. Microglia engulf lipofuscin and lipofuscin-containing neurons. Notably, conventional or conditional knockout mice lacking CSPα/DNAJC5 did not exhibit any signs of increased lipofuscinosis or GRODs. Our novel mouse models provide a valuable tool to investigate the molecular mechanisms underlying Kufs disease/CLN4. DNAJC5 mutations cause neuronal lipofuscinosis through a cell-autonomous gain of a pathological function of CSPα/DNAJC5.