biostudies-literatureUnknown11(21)Lopez-Begines SKufs disease/CLN4 is an autosomal dominant neurodegenerative disorder caused by unknown mechanisms through Leu¹¹⁵Arg and Leu¹¹⁶Δ 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), Leu¹¹⁵Arg, and Leu¹¹⁶Δ. Mice expressing mutant Leu¹¹⁵Arg 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 Science advanceseads3393https://www.ebi.ac.uk/biostudies/studies/S-EPMC12094229biostudies-literatureNeuronal lipofuscinosis caused by Kufs disease/CLN4 DNAJC5 mutations but not by a CSPα/DNAJC5 deficiency.PMC12094229Lavado-Roldan AChiclana-Valcarcel MLMesa-Cruz CLujan RWiersma VIBorjini NRubio-Pastor FTumini EMavillard FFernandez-Chacon RParadela-Leal CScheper WLopez-Begines SAguado CNieto-Gonzalez JLfalseNeuronal 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 Leu¹¹⁵Arg and Leu¹¹⁶Δ 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), Leu¹¹⁵Arg, and Leu¹¹⁶Δ. Mice expressing mutant Leu¹¹⁵Arg 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 2025-01-01T00:00:00Z2025 May2026-06-01T10:24:05.062Z2026-04-08T11:26:57.073ZS-EPMC120942294039774010.1126/sciadv.ads3393