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Treatments are emerging for the neuronal ceroid lipofuscinoses (NCLs), a group of similar but genetically distinct lysosomal storage diseases. Clinical ratings scales measure long-term disease progression and response to treatment but clinically useful biomarkers have yet to be identified in these diseases. We have conducted proteomic analyses of brain and cerebrospinal fluid (CSF) from mouse models of the most frequently diagnosed NCL diseases: CLN1 (infantile NCL), CLN2 (classical late infantile NCL) and CLN3 (juvenile NCL). Samples were obtained at different stages of disease progression and proteins quantified using isobaric labeling. In total, 8303 and 4905 proteins were identified from brain and CSF, respectively. We also conduced label-free analyses of brain proteins that contained the mannose 6-phosphate lysosomal targeting modification. In general, we detect few changes at presymptomatic timepoints but later in disease, we detect multiple proteins whose expression is significantly altered in both brain and CSF of CLN1 and CLN2 animals. Many of these proteins are lysosomal in origin or are markers of neuroinflammation, potentially providing clues to underlying pathogenesis and providing promising candidates for further validation. Show less

Mutations in at least 13 different genes (called CLNs) underlie various forms of neuronal ceroid lipofuscinoses (NCLs), a group of the most common neurodegenerative lysosomal storage diseases. While inactivating mutations in the CLN1 gene, encoding palmitoyl-protein thioesterases-1 (PPT1), cause infantile NCL (INCL), those in the CLN3 gene, encoding a protein of unknown function, underlie juvenile NCL (JNCL). PPT1 depalmitoylates S-palmitoylated proteins (constituents of ceroid) required for their degradation by lysosomal hydrolases and PPT1-deficiency causes lysosomal accumulation of autofluorescent ceroid leading to INCL. Because intracellular accumulation of ceroid is a characteristic of all NCLs, a common pathogenic link for these diseases has been suggested. It has been reported that CLN3-mutations suppress the exit of cation-independent mannose 6-phosphate receptor (CI-M6PR) from the trans Golgi network (TGN). Because CI-M6PR transports soluble proteins such as PPT1 from the TGN to the lysosome, we hypothesized that CLN3-mutations may cause lysosomal PPT1-insufficiency contributing to JNCL pathogenesis. Here, we report that the lysosomes in Cln3-mutant mice, which mimic JNCL, and those in cultured cells from JNCL patients, contain significantly reduced levels of Ppt1-protein and Ppt1-enzyme activity and progressively accumulate autofluorescent ceroid. Furthermore, in JNCL fibroblasts the V0a1 subunit of v-ATPase, which regulates lysosomal acidification, is mislocalized to the plasma membrane instead of its normal location on lysosomal membrane. This defect dysregulates lysosomal acidification, as we previously reported in Cln1 Show less

In the unicellular eukaryote Saccharomyces cerevisiae, Cln3-cyclin-dependent kinase activity enables Start, the irreversible commitment to the cell division cycle. However, the concentration of Cln3 has been paradoxically considered to remain constant during G1, due to the presumed scaling of its production rate with cell size dynamics. Measuring metabolic and biosynthetic activity during cell cycle progression in single cells, we found that cells exhibit pulses in their protein production rate. Rather than scaling with cell size dynamics, these pulses follow the intrinsic metabolic dynamics, peaking around Start. Using a viral-based bicistronic construct and targeted proteomics to measure Cln3 at the single-cell and population levels, we show that the differential scaling between protein production and cell size leads to a temporal increase in Cln3 concentration, and passage through Start. This differential scaling causes Start in both daughter and mother cells across growth conditions. Thus, uncoupling between two fundamental physiological parameters drives cell cycle commitment. Show less

Neuronal ceroid lipofuscinoses are neurodegenerative disorders. To investigate the diagnostic yield of direct Sanger sequencing of the We reviewed electronic patient charts. We used consent forms and Research Electronic Data Capture questionnaires for the patients from outside of our Institution. We reclassified all variants in the Six hundred and ninety three individuals underwent the direct Sanger sequencing of the In our study, the diagnostic yield of direct Sanger sequencing was close to diagnostic yield of whole exome sequencing. Developmental regression, cognitive decline, visual impairment and cerebral and/or cerebellar atrophy in brain MRI are significant clinical and neuroimaging denominators to include NCL in the differential diagnosis. Show less

Alterations in the autophagosomal-lysosomal pathway are a major pathophysiological feature of CLN3 disease, which is the most common form of childhood-onset neurodegeneration. Accumulating autofluorescent lysosomal storage material in CLN3 disease, consisting of dolichols, lipids, biometals, and a protein that normally resides in the mitochondria, subunit c of the mitochondrial ATPase, provides evidence that autophagosomal-lysosomal turnover of cellular components is disrupted upon loss of CLN3 protein function. Using a murine neuronal cell model of the disease, which accurately mimics the major gene defect and the hallmark features of CLN3 disease, we conducted an unbiased search for modifiers of autophagy, extending previous work by further optimizing a GFP-LC3 based assay and performing a high-content screen on a library of ~2000 bioactive compounds. Here we corroborate our earlier screening results and identify expanded, independent sets of autophagy modifiers that increase or decrease the accumulation of autophagosomes in the CLN3 disease cells, highlighting several pathways of interest, including the regulation of calcium signaling, microtubule dynamics, and the mevalonate pathway. Follow-up analysis on fluspirilene, nicardipine, and verapamil, in particular, confirmed activity in reducing GFP-LC3 vesicle burden, while also demonstrating activity in normalizing lysosomal positioning and, for verapamil, in promoting storage material clearance in CLN3 disease neuronal cells. This study demonstrates the potential for cell-based screening studies to identify candidate molecules and pathways for further work to understand CLN3 disease pathogenesis and in drug development efforts. Show less

Objective To investigate the effect of Legionella pneumophila (LP) on the autophagy flux of RAW264.7 macrophages and explore the molecular mechanism of the expression changes of autophagy-related factors. Methods Live LP and inactivated LP (MOI=10, 50, 100) were separately used to affect RAW264.7 for 1, 2 and 3 hours so as to screen the optimum condition of LP infection. The optimal condition for LP infection was MOI=50 and the infection time was 2 hours. After affected by rapamycin (RAPA) for 12 hours, RAW264.7 cells were then treated by live and inactivated LP for another 2 hours. Normal control group, RAPA group, live LP group, inactivated LP group, RAPA-treated live LP group, RAPA-treated inactivated LP group were designed. The pmCherry-C1-EGFP-LC3B double fluorescent labeling protein method was used to monitor the changes of autophagy flux. The relevant factor CLN3, histone deacetylase 6 (HDAC6), regulator of G protein signaling 19 (RGS19), tumor necrosis factor (TNF), cathepsin B (CTSB), GABA type A receptor associated protein like 2 (GABARAPL2), P62, microtubule-related protein 1 light chain 3 (LC3) were screened by gene array analysis. In order to validate the results of gene array, real-time quantitative PCR (RT-qPCR) was used to detect the mRNA levels of nuclear factor erythroid derived 2 like 2 (Nrf2), beclin1 and kelch like ECH associated protein 1 (Keap1); Western blot analysis was performed to measure the protein levels of Nrf2, beclin1 and Keap1. Results Both the live LP group and the inactivated LP group inhibited the autophagy flux compared with the normal control group and the RAPA group. Gene array analysis showed that in the live LP and inactivated LP groups, LC3 expression was down-regulated and P62 expression was up-regulated. The results of RT-qPCR and Western blot analysis were consistent with the gene array. The mRNA and protein levels of Keap1, beclin1, and Nrf2 significantly decreased, while the mRNA and protein levels of Nrf2 significantly increased. Conclusion LP can inhibit the autophagy of macrophage via activating Nrf2-Keap1 signaling pathway. Show less

Mattapallil et al. described that vendor lines for C57BL/6 N mice may carry the rd8 mutation that leads to an ocular phenotype, which could be mistaken for an induced retinal degeneration. This mouse strain is widely used in ophthalmic research as a background for modeling retinal degeneration. In the process of studying Cln3 Show less

The juvenile form of neuronal ceroid Lipofuscinosis (JNCL) is the most common form within this group of rare lysosomal storage disorders, causing pediatric neurodegeneration. The genetic disorder, which is caused by recessive mutations affecting the CLN3 gene, features progressive vision loss, cognitive and motor decline and other psychiatric conditions, seizure episodes, leading to premature death. Animal models have traditionally aid the understanding of the disease mechanisms and pathology and are very relevant for biomarker research and therapeutic testing. Nevertheless, there is a need for establishing reliable and predictive human cellular models to study the disease. Since patient material, particularly from children, is scarce and difficult to obtain, we generated an engineered a CLN3-mutant isogenic human induced pluripotent stem cell (hiPSC) line carrying the c.1054C → T pathologic variant, using state of the art CRISPR/Cas9 technology. To prove the suitability of the isogenic pair to model JNCL, we screened for disease-specific phenotypes in non-neuronal two-dimensional cell culture models as well as in cerebral brain organoids. Our data demonstrates that the sole introduction of the pathogenic variant gives rise to classical hallmarks of JNCL in vitro. Additionally, we discovered an alteration of the splicing caused by this particular mutation. Next, we derived cerebral organoids and used them as a neurodevelopmental model to study the particular effects of the CLN3 Show less

One of the most important steps taken by Beyond Batten Disease Foundation in our quest to cure juvenile Batten (CLN3) disease is to understand the State of the Science. We believe that a strong understanding of where we are in our experimental understanding of the CLN3 gene, its regulation, gene product, protein structure, tissue distribution, biomarker use, and pathological responses to its deficiency, lays the groundwork for determining therapeutic action plans. To present an unbiased comprehensive reference tool of the experimental understanding of the CLN3 gene and gene product of the same name. BBDF compiled all of the available CLN3 gene and protein data from biological databases, repositories of federally and privately funded projects, patent and trademark offices, science and technology journals, industrial drug and pipeline reports as well as clinical trial reports and with painstaking precision, validated the information together with experts in Batten disease, lysosomal storage disease, lysosome/endosome biology. The finished product is an indexed review of the CLN3 gene and protein which is not limited in page size or number of references, references all available primary experiments, and does not draw conclusions for the reader. Revisiting the experimental history of a target gene and its product ensures that inaccuracies and contradictions come to light, long-held beliefs and assumptions continue to be challenged, and information that was previously deemed inconsequential gets a second look. Compiling the information into one manuscript with all appropriate primary references provides quick clues to which studies have been completed under which conditions and what information has been reported. This compendium does not seek to replace original articles or subtopic reviews but provides an historical roadmap to completed works. Show less

The neuronal ceroid lipofuscinoses (NCLs) are a group of devastating neurological disorders that have a global distribution and affect people of all ages. Commonly known as Batten disease, this form of neurodegeneration is linked to mutations in 13 genetically distinct genes. The precise mechanisms underlying the disease are unknown, in large part due to our poor understanding of the functions of NCL proteins. The social amoeba Show less

Lignocellulosic ethanol production requires high substrate concentrations for its cost-competitiveness. This implies the presence of high concentrations of insoluble solids (IS) at the initial stages of the process, which may limit the fermentation performance of the corresponding microorganism. The presence of 40-60% IS (w/w) resulted in lower glucose consumption rates and reduced ethanol volumetric productivities of Saccharomyces cerevisiae F12. Yeast cells exposed to IS exhibited a wrinkled cell surface and a reduced mean cell size due to cavity formation. In addition, the intracellular levels of reactive oxygen species (ROS) increased up to 40%. These ROS levels increased up to 70% when both lignocellulose-derived inhibitors and IS were simultaneously present. The general stress response mechanisms (e.g. DDR2, TPS1 or ZWF1 genes, trehalose and glycogen biosynthesis, and DNA repair mechanisms) were found repressed, and ROS formation could not be counteracted by the induction of the genes involved in repairing the oxidative damage such as glutathione, thioredoxin and methionine scavenging systems (e.g. CTA1, GRX4, MXR1, and TSA1; and the repression of cell cycle progression, CLN3). Overall, these results clearly show the role of IS as an important microbial stress factor that affect yeast cells at physical, physiological, and molecular levels. Show less

The precise coordination of growth and proliferation has a universal prevalence in cell homeostasis. As a prominent property, cell size is modulated by the coordination between these processes in bacterial, yeast, and mammalian cells, but the underlying molecular mechanisms are largely unknown. Here, we show that multifunctional chaperone systems play a concerted and limiting role in cell-cycle entry, specifically driving nuclear accumulation of the G1 Cdk-cyclin complex. Based on these findings, we establish and test a molecular competition model that recapitulates cell-cycle-entry dependence on growth rate. As key predictions at a single-cell level, we show that availability of the Ydj1 chaperone and nuclear accumulation of the G1 cyclin Cln3 are inversely dependent on growth rate and readily respond to changes in protein synthesis and stress conditions that alter protein folding requirements. Thus, chaperone workload would subordinate Start to the biosynthetic machinery and dynamically adjust proliferation to the growth potential of the cell. Show less

Oscillating gene expression is crucial for correct timing and progression through cell cycle. In Saccharomyces cerevisiae, G1 cyclins Cln1-3 are essential drivers of the cell cycle and have an important role for temporal fine-tuning. We measured time-resolved transcriptome-wide gene expression for wild type and cyclin single and double knockouts over cell cycle with and without osmotic stress. Clustering of expression profiles, peak time detection of oscillating genes, integration with transcription factor network dynamics, and assignment to cell cycle phases allowed us to quantify the effect of genetic or stress perturbations on the duration of cell cycle phases. Cln1 and Cln2 showed functional differences, especially affecting later phases. Deletion of Cln3 led to a delay of START followed by normal progression through later phases. Our data and network analysis suggest mutual effects of cyclins with the transcriptional regulators SBF and MBF. Show less

Loss of proteostasis and cellular senescence are key hallmarks of aging, but direct cause-effect relationships are not well understood. We show that most yeast cells arrest in G1 before death with low nuclear levels of Cln3, a key G1 cyclin extremely sensitive to chaperone status. Chaperone availability is seriously compromised in aged cells, and the G1 arrest coincides with massive aggregation of a metastable chaperone-activity reporter. Moreover, G1-cyclin overexpression increases lifespan in a chaperone-dependent manner. As a key prediction of a model integrating autocatalytic protein aggregation and a minimal Start network, enforced protein aggregation causes a severe reduction in lifespan, an effect that is greatly alleviated by increased expression of specific chaperones or cyclin Cln3. Overall, our data show that proteostasis breakdown, by compromising chaperone activity and G1-cyclin function, causes an irreversible arrest in G1, configuring a molecular pathway postulating proteostasis decay as a key contributing effector of cell senescence. Show less

Multi-gene panel testing is used increasingly in ophthalmology practice as an efficient and cost-effective method for diagnosing inherited eye conditions. Panel testing is a powerful diagnostic tool, and it has the potential to reveal syndromic information in patients with seemingly isolated eye findings. This case series highlights our experience with 4 children in 3 families who were referred for evaluation of an isolated retinal degeneration and diagnosed with neuronal ceroid lipofuscinosis on panel testing. These cases are important reminders that several neurodegenerative conditions can present initially with isolated eye findings in childhood and pretest genetic counseling is critical. Show less

To delineate timing of motor decline in CLN3 disease. Motor function, assessed by the 6-Minute Walk Test (6MWT), was evaluated repeatedly in 15 patients with CLN3 disease, resulting in 65 test results and during one occasion in 2 control cohorts. One control cohort (n = 14) had isolated visual impairment; a second cohort (n = 12) exhibited visual impairment in combination with neurologic impairments. Based on 6MWT reference values in healthy sighted children, In CLN3 disease, 6MWT scores were already impaired from first testing near diagnosis (mean The 6MWT unveils early onset of motor decline in CLN3 disease. Show less

CLN3 disease is the commonest of the neuronal ceroid lipofuscinoses, a group of pediatric neurodegenerative disorders. Functions of the CLN3 protein include antiapoptotic properties and facilitating anterograde transport of galactosylceramide from Golgi to lipid rafts. This study confirms the beneficial effects of long-term exogenous galactosylceramide supplementation on longevity, neurobehavioral parameters, neuronal cell counts, astrogliosis, and diminution in brain and serum ceramide levels in Cln3 A group of 72 mice received galactosylceramide or vehicle for 40 weeks. The effect of galactosylceramide supplementation on Cln3 Galactosylceramide resulted in enhanced grip strength of forelimbs in male and female mice, better balance on the accelerating rotarod in females, and improved motor coordination during pole climbing in male mice. Brain and serum ceramide levels as well as apoptosis rates were lower in galactosylceramide-treated Cln3 Galactosylceramide improved behavioral, neuropathological, and biochemical parameters in Cln3 Show less

The aberrant expression of ceroid-lipofuscinosis 3 (CLN3) has been reported in a variety of human malignancies. However, the role of CLN3 in the progression and prognosis of hepatocellular carcinoma (HCC) remains unknown. In this study, we found that CLN3 was frequently upregulated in HCC clinical samples and HCC-derived cell lines and was significantly correlated with an APF serum level ≥20 μg/L, a tumour size ≥5 cm, multiple tumours, and the absence of encapsulation. Kaplan-Meier showed that CLN3 upregulation predicted shorter recurrence-free survival (RFS) and overall survival (OS) time in HCC patients. Cox regression analysis revealed that CLN3 upregulation was an independent risk factor for RFS and OS. A functional study demonstrated that the knockdown of CLN3 expression profoundly suppressed the growth and metastasis of HCC cells both in vitro and in vivo. Mechanistic investigation revealed that the EGFR/PI3K/AKT pathway was essential for mediating CLN3 function. In conclusion, our results provide the first evidence that CLN3 contributes to tumour progression and metastasis and offer a potential prognostic predictor and therapeutic target for HCC. Show less

Mutations in CLN3 cause a juvenile form of neuronal ceroid lipofuscinosis (NCL). This devastating neurological disorder, commonly known as Batten disease, is currently untreatable due to a lack of understanding of the physiological role of the protein. Recently, work in the social amoeba Dictyostelium discoideum has provided valuable new insight into the function of CLN3 in the cell. More specifically, research has linked the Dictyostelium homolog (gene: cln3, protein: Cln3) to protein secretion, adhesion, and aggregation during starvation, which initiates multicellular development. In this study, we used comparative transcriptomics to explore the mechanisms underlying the aberrant response of cln3 Show less

Embryonic developmental stages and regulations have always been one of the most intriguing aspects of science. Since the cancer stem cell discovery, striking for cancer development and recurrence, embryonic stem cells and control mechanisms, as well as cancer cells and cancer stem cell control mechanisms become important research materials. It is necessary to reveal the similarities and differences between somatic and cancer cells which are formed of embryonic stem cells divisions and determinations. For this purpose, mouse embryonic stem cells (mESCs), mouse skin fibroblast cells (MSFs) and mouse lung squamous cancer cells (SqLCCs) were grown in vitro and the differences between these three cell lines signalling regulations of mechanistic target of rapamycin (mTOR) and autophagic pathways were demonstrated by immunofluorescence and real-time polymerase chain reaction. Expressional differences were clearly shown between embryonic, cancer and somatic cells that mESCs displayed higher expressional level of Atg10, Hdac1 and Cln3 which are related with autophagic regulation and Hsp4, Prkca, Rhoa and ribosomal S6 genes related with mTOR activity. LC3 and mTOR protein levels were lower in mESCs than MSFs. Thus, the mechanisms of embryonic stem cell regulation results in the formation of somatic tissues whereas that these cells may be the causative agents of cancer in any deterioration. Show less

Travel burden often substantially limits the ability of individuals to participate in clinical trials. Wide geographic dispersion of individuals with rare diseases poses an additional key challenge in the conduct of clinical trials for rare diseases. Novel technologies and methods can improve access to research by connecting participants in their homes and local communities to a distant research site. For clinical trials, however, understanding of factors important for transition from traditional multi-center trial models to local participation models is limited. We sought to test a novel, hybrid, single- and multi-site clinical trial design in the context of a trial for Juvenile Neuronal Ceroid Lipofuscinosis (CLN3 disease), a very rare pediatric neurodegenerative disorder. We created a "hub and spoke" model for implementing a 22-week crossover clinical trial of mycophenolate compared with placebo, with two 8-week study arms. A single central site, the "hub," conducted screening, consent, drug dispensing, and tolerability and efficacy assessments. Each participant identified a clinician to serve as a collaborating "spoke" site to perform local safety monitoring. Study participants traveled to the hub at the beginning and end of each study arm, and to their individual spoke site in the intervening weeks. A total of 18 spoke sites were established for 19 enrolled study participants. One potential participant was unable to identify a collaborating local site and was thus unable to participate. Study start-up required a median 6.7 months (interquartile range = 4.6-9.2 months). Only 33.3% (n = 6 of 18) of spoke site investigators had prior clinical trial experience, thus close collaboration with respect to study startup, training, and oversight was an important requirement. All but one participant completed all study visits; no study visits were missed due to travel requirements. This study represents a step toward local trial participation for patients with rare diseases. Even in the context of close oversight, local participation models may be best suited for studies of compounds with well-understood side-effect profiles, for those with straightforward modes of administration, or for studies requiring extended follow-up periods. Show less

Neuronal ceroid lipofuscinoses (NCLs; CLN) are mainly autosomal recessive neurodegenerative disorders characterized by the accumulation of autofluorescent lipopigments in neuronal and other cells. Symptoms include visual disabilities, motor decline, and epilepsy. Causative genes are CLN1, CLN2, CLN3, CLN5, CLN6, CLN7, CLN8, CLN10, CLN11, CLN12, CLN13, and CLN14. We present the fourth Japanese case with a CLN6 mutation. At 3 years of age, our patient became clumsy and fell down easily. He developed focal seizures with impaired consciousness and was started on carbamazepine. He showed ataxic walking and dysarthria with increased deep tendon reflexes. Interictal electroencephalogram revealed slow waves in the left temporal and occipital areas. Brain magnetic resonance imaging showed cerebellar atrophy and ventriculomegaly. In optical coherence tomography (OCT), the inner layer of the retina was thick and highly reflective. Exome sequencing revealed a known homozygous mutation, C.794₉₇₆del, p. (Ser265del) in CLN6. A total of 130 cases of NCL with CLN6 mutations have been reported globally, of which only four were from Japan including the current patient. The deletion of serine at position 265 has been reported in six cases. Ser265 is located in a region of short repeated sequences that is susceptible to mutation. Clinical trials of gene therapy using adeno-associated virus serotype 9 have started for NCL6, making early diagnosis crucial. OCT examination might be helpful in achieving a diagnosis. Show less

Juvenile neuronal ceroid lipofuscinosis (CLN3 disease) is the most common neurodegenerative disorder in childhood with survival until young adult age. Visual loss is followed by epilepsy, cognitive, neuropsychiatric, and motor symptoms. We have studied the evolution of electroencephalographic (EEG) and seizure characteristics. Twenty-four patients were recruited via the Norwegian CLN3 disease parent association. Parents were interviewed. Medical records and EEG reports/recordings were collected. Electroencephalographic elements were classified according to Standardized computer-based organized reporting of EEG (SCORE). The evolution of EEG features along with seizure types was assessed by testing the difference in proportions with standardized normal deviate comparing findings below and above 15 years of age. Mean age at study or death (n = 12) was 21.2 (10-39) years. Twenty-two patients had experienced seizures; the first was usually bilateral tonic-clonic (TC). Later, focal motor seizures frequently occurred, often with increasing multifocal and polymorphic features. Paroxysmal nonepileptic motor and autonomous symptoms were also suspected in several patients. Distinct myoclonic seizures were uncommon. In four patients, we identified episodes of bradycardia/sinus arrest. Electroencephalography showed progressive slowing of the background activity (p = 0.029). Focal epileptiform discharges were rare and mainly seen at age <10. Combined multifocal and bilateral epileptiform discharges increased in adolescence (p = 0.002). Seizure and EEG characteristics change with time in CLN3 disease. Tonic-clonic seizures are common at onset, and multifocal motor seizures increase with age. In contrast, focal epileptiform abnormalities are more common in childhood, compared to later multifocal and bilateral discharges. This seizure disorder belongs to the combined generalized and focal epilepsies. Paucity of myoclonic seizures does not warrant classification as a classic progressive myoclonic epilepsy. When attacks with only behavior arrest occur, cardiac conduction abnormalities should be considered. Show less

CLN3 disease is a neurodevelopmental disease leading to early visual failure, motor decline, and death. CLN3 pathogenesis has been linked to dysregulation of ceramide, a key intracellular messenger impacting various biological functions. Ceramide is upregulated in brains of CLN3 patients and activates apoptosis. Ceramide levels over the lifespan of WT and Show less

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 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. 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 Show less