Loss of CLN3 the gene mutated in juvenile neuronal ceroid lipofuscinosis leads to metabolic impairment and autophagy induction in retinal pigment epithelium.
Sine the discovery of juvenile Batten disease many discoveries have been made relevant to the CLN3 gene its protein regulation or dysfunction. However the function of CLN3 protein remains elusive and many questions remain as to why CLN3 gene defects adversely affect endosomal-lysosomal homeostasis proteome lipidome trafficking maturation and recycling activities. (review)
Cln3-mutations underlying juvenile neuronal ceroid lipofuscinosis cause significantly reduced levels of Palmitoyl-protein thioesterases-1 (Ppt1)-protein and Ppt1-enzyme activity in the lysosome.
Our case study shows that (1) non-syndromic CLN3 disease leads to rod and delayed primary cone degeneration resulting in constricting peripheral field and enlarging central scotoma and (2) the c.175G>A CLN3 mutation altered splicing of the CLN3 gene.
We describe a patient who initially presented with CLN3-associated isolated retinal degeneration but developed adult-onset neurologic decline contrasting with the previous exclusive association of the R405W mutation with isolated vision loss.
The age at onset and natural progression of retinal disease differs greatly between syndromic and nonsyndromic CLN3 disease which may be associated with genotypic differences.
The lysosomal enzyme cathepsin D (CTSD) mediates the proteolytic cleavage of PSAP precursor into saposins A-D. Myc-CLN3 colocalized with CTSD and activity of CTSD decreased as myc-CLN3 expression increased and clearly decreased under hyperosmotic conditions
the results of this study indicate that Cln3 functions in both conventional and unconventional protein secretion and that loss of Cln3 results in deregulated secretion during early development. Importantly this is the first evidence in any system linking CLN3 function to protein secretion.
AAV2-CLN3 was efficacious in restoring full-length CLN3 transcript and protein in patient-specific fibroblasts and iPSC-derived retinal neurons. When injected into the subretinal space of wild-type mice purified AAV2-CLN3 did not show any evidence of retinal toxicity
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