Neuronal lipofuscinosis caused by Kufs disease/CLN4 DNAJC5 mutations but not by a CSP alpha/DNAJC5 deficiency

DescriptionKufs disease/CLN4 is an autosomal dominant neurodegenerative disorder caused by unknown mechanisms through Leu115Arg and Leu116Delta mutations in the DNAJC5 gene that encodes the synaptic vesicle co-chaperone Cysteine String Protein a (CSP alpha/DNAJC5). To investigate the disease mechanisms in vivo, we generated three independent mouse lines overexpressing different versions of CSP alpha/DNAJC5 under the neuron-specific Thy1 promoter: wild-type (WT), Leu115Arg, and Leu116Delta. Mice expressing mutant Leu115Arg CSP alpha/DNAJC5 are viable but develop motor deficits. As described in Kufs disease patients, 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 CSP alpha/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 novel, but pathological, function of CSP alpha/DNAJC5.More info at: doi: https://doi.org/10.1101/2023.05.10.540177