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Oligomerization of Cysteine String Protein alpha mutants causing adult neuronal ceroid lipofuscinosis.

ABSTRACT: Cysteine String Protein alpha (CSP?) is a palmitoylated, synaptic vesicle co-chaperone that is essential for neuroprotection. Two mutations in CSP? - L115R and L116? - cause adult neuronal ceroid lipofuscinosis (ANCL), a dominantly-inherited neurodegenerative disease. To elucidate the pathogenesis of ANCL, the intrinsic biochemical properties of human wildtype (WT) and disease mutant CSP? were examined. Mutant proteins purified from Escherichia coli exhibited high potency to oligomerize in a concentration, temperature, and time dependent manner, with L115R possessing the greatest potency. When freshly purified, ANCL mutant proteins displayed normal co-chaperone activity and substrate recognition similar to WT. However, co-chaperone activity was impaired for both CSP? mutants upon oligomerization. When WT and mutant CSP? were mixed together they co-oligomerized leading to an overall decrease of co-chaperone activity. The oligomerization properties of ANCL mutants were faithfully replicated in HEK 293T cells. Interestingly, the oligomers were covalently tagged by ubiquitination instead of palmitoylation. Taken together, ANCL mutations result in both a gain and partial loss-of-function.

SUBMITTER: Zhang YQ

PROVIDER: S-EPMC4188699 | biostudies-other | 2014 Nov

REPOSITORIES: biostudies-other

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Oligomerization of Cysteine String Protein alpha mutants causing adult neuronal ceroid lipofuscinosis.

Zhang Yong-Quan YQ Chandra Sreeganga S SS

Biochimica et biophysica acta 20140723 11

Cysteine String Protein alpha (CSPα) is a palmitoylated, synaptic vesicle co-chaperone that is essential for neuroprotection. Two mutations in CSPα - L115R and L116Δ - cause adult neuronal ceroid lipofuscinosis (ANCL), a dominantly-inherited neurodegenerative disease. To elucidate the pathogenesis of ANCL, the intrinsic biochemical properties of human wildtype (WT) and disease mutant CSPα were examined. Mutant proteins purified from Escherichia coli exhibited high potency to oligomerize in a con ...[more]

PMID: 25064588

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Project description:We performed whole-exome sequencing in two autopsy-confirmed cases and an elderly unaffected control from a multigenerational family with autosomal dominant neuronal ceroid lipofuscinosis (ANCL). A novel single-nucleotide variation (c.344T>G) in the DNAJC5 gene was identified. Mutational screening in an independent family with autosomal dominant ANCL found an in-frame single codon deletion (c.346_348 delCTC) resulting in a deletion of p.Leu116del. These variants fulfill all genetic criteria for disease-causing mutations: they are found in unrelated families with the same disease, exhibit complete segregation between the mutation and the disease, and are absent in healthy controls. In addition, the associated amino acid substitutions are located in evolutionarily highly conserved residues and are predicted to functionally affect the encoded protein (CSP?). The mutations are located in a cysteine-string domain, which is required for membrane targeting/binding, palmitoylation, and oligomerization of CSP?. We performed a comprehensive in silico analysis of the functional and structural impact of both mutations on CSP?. We found that these mutations dramatically decrease the affinity of CSP? for the membrane. We did not identify any significant effect on palmitoylation status of CSP?. However, a reduction of CSP? membrane affinity may change its palmitoylation and affect proper intracellular sorting. We confirm that CSP? has a strong intrinsic aggregation propensity; however, it is not modified by the mutations. A complementary disease-network analysis suggests a potential interaction with other NCLs genes/pathways. This is the first replication study of the identification of DNAJC5 as the disease-causing gene for autosomal dominant ANCL. The identification of the novel gene in ANCL will allow us to gain a better understanding of the pathological mechanism of ANCLs and constitutes a great advance toward the development of new molecular diagnostic tests and may lead to the development of potential therapies.

Project description: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 coveredThe 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 opinionMuch 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.

Project description:The present review is focused on juvenile neuronal ceroid lipofuscinosis (JNCL; Batten disease) due to a mutation in CLN3. Functional vision impairment occurring around 5-6 years of age is the first symptom in more than 80% of patients. Approximately 2 years later (though sometimes simultaneously), obvious signs of cognitive impairment appear. Behavior problems can occur in advance, especially in boys. These include anxious and depressed mood, aggressive behavior, and hallucinations, and even psychotic symptoms. Following the teens, severe dementia is present, including loss of memory, attention, and general reasoning abilities, as well as loss of independent adaptive skills such as mobility, feeding, and communicating. Sleep abnormalities, such as settling problems, nocturnal awakenings, and nightmares, are reported in more than half of patients. The vast majority, if not all, patients develop seizures, starting at approximately 10 years of age. Generalized tonic-clonic seizure occurs as the only type of seizure in approximately half of patients, and in combination with partial seizures in a third of patients. There seems to be no difference in seizure severity according to sex or genotype, and there is great variation in seizure activity among patients. Soon after diagnosis, patients begin to have slight ataxic symptoms, and at adolescence extrapyramidal symptoms (rigidity, bradykinesia, slow steps with flexion in hips and knees) occur with increasing frequency. Chewing and swallowing difficulties emerge as well, and food intake is hampered in the late teens. Disabling periodically involuntary movements may occur as well. A progressive cardiac involvement with repolarization disturbances, ventricular hypertrophy, and sinus-node dysfunction, ultimately leading to severe bradycardia and/or other conduction abnormalities, starts in the mid-teens. Patients are usually bedridden at 20 years of age, and death usually occurs in the third decade of life.

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Oligomerization of Cysteine String Protein alpha mutants causing adult neuronal ceroid lipofuscinosis.

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Oligomerization of Cysteine String Protein alpha mutants causing adult neuronal ceroid lipofuscinosis.

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