RESUMEN
Neuronal ceroid lipofuscinoses (NCL) represent a class of neurodegenerative disorders involving defective lysosomal processing enzymes or receptors, leading to lysosomal storage disorders, typically characterized by observation of cognitive and visual impairments, epileptic seizures, ataxia, and deterioration of motor skills. Recent success of a biologic (Brineura®) for the treatment of neurologic manifestations of the central nervous system (CNS) has led to renewed interest in therapeutics for NCL, with the goal of ablating or reversing the impact of these devastating disorders. Despite complex challenges associated with CNS therapy, many treatment modalities have been evaluated, including enzyme replacement therapy, gene therapy, stem cell therapy, and small molecule pharmacotherapy. Because the clinical endpoints for the evaluation of candidate therapies are complex and often reliant on subjective clinical scales, the development of quantitative biomarkers for NCLs has become an apparent necessity for the validation of potential treatments. We will discuss the latest findings in the search for relevant biomarkers for assessing disease progression. For this review, we will focus primarily on recent pre-clinical and clinical developments for treatments to halt or cure these NCL diseases. Continued development of current therapies and discovery of newer modalities will be essential for successful therapeutics for NCL. AREAS COVERED: The reader will be introduced to the NCL subtypes, natural histories, experimental animal models, and biomarkers for NCL progression; challenges and different therapeutic approaches, and the latest pre-clinical and clinical research for therapeutic development for the various NCLs. This review corresponds to the literatures covering the years from 1968 to mid-2019, but primarily addresses pre-clinical and clinical developments for the treatment of NCL disease in the last decade and as a follow-up to our 2013 review of the same topic in this journal. EXPERT OPINION: Much progress has been made in the treatment of neurologic diseases, such as the NCLs, including better animal models and improved therapeutics with better survival outcomes. Encouraging results are being reported at symposiums and in the literature, with multiple therapeutics reaching the clinical trial stage for the NCLs. The potential for a cure could be at hand after many years of trial and error in the preclinical studies. The clinical development of enzyme replacement therapy (Brineura® for CLN2), immunosuppression (CellCept® for CLN3), and gene therapy vectors (for CLN1, CLN2, CLN3, and CLN6) are providing encouragement to families that have a child afflicted with NCL. We believe that successful therapies in the future may involve the combination of two or more therapeutic modalities to provide therapeutic benefit especially as the patients grow older.
RESUMEN
Neuronal ceroid lipofuscinoses (NCL) are a group of inherited neurodegenerative disorders with lysosomal pathology (CLN1-14). Recently, mutations in the DNAJC5/CLN4 gene, which encodes the presynaptic co-chaperone CSPα were shown to cause autosomal-dominant NCL. Although 14 NCL genes have been identified, it is unknown if they act in common disease pathways. Here we show that two disease-associated proteins, CSPα and the depalmitoylating enzyme palmitoyl-protein thioesterase 1 (PPT1/CLN1) are biochemically linked. We find that in DNAJC5/CLN4 patient brains, PPT1 is massively increased and mis-localized. Surprisingly, the specific enzymatic activity of PPT1 is dramatically reduced. Notably, we demonstrate that CSPα is depalmitoylated by PPT1 and hence its substrate. To determine the consequences of PPT1 accumulation, we compared the palmitomes from control and DNAJC5/CLN4 patient brains by quantitative proteomics. We discovered global changes in protein palmitoylation, mainly involving lysosomal and synaptic proteins. Our findings establish a functional link between two forms of NCL and serve as a springboard for investigations of NCL disease pathways.