Upregulation of tripeptidyl-peptidase 1 by 3-hydroxy-(2,2)-dimethyl butyrate, a brain endogenous ligand of PPARα: Implications for late-infantile Batten disease therapy.

The late-infantile Batten disease or late-infantile neuronal ceroid lipofuscinosis (LINCL) is an autosomal recessive lysosomal storage disorder caused by mutations in the Cln2 gene leading to deficiency of lysosomal enzyme tripeptidyl peptidase 1 (TPP1). At present, available options for this fatal disorder are enzyme replacement therapy and gene therapy, which are extensively invasive and expensive. Our study demonstrates that 3-hydroxy-(2,2)-dimethyl butyrate (HDMB), a brain endogenous molecule, is capable of stimulating TPP1 expression and activity in mouse primary astrocytes and a neuronal cell line. HDMB activated peroxisome proliferator-activated receptor-α (PPARα), which, by forming heterodimer with Retinoid X receptor-α (RXRα), transcriptionally upregulated the Cln2 gene. Moreover, by using primary astrocytes from wild type, PPARα-/- and PPARß-/- mice, we demonstrated that HDMB specifically required PPARα for inducing TPP1 expression. Finally, oral administration of HDMB to Cln2 heterozygous (Cln2+/-) mice led to a marked upregulation of TPP1 expression in the motor cortex and striatum in a PPARα-dependent fashion. Our study suggests that HDMB, a brain endogenous ligand of PPARα, might have therapeutic importance for LINCL treatment.

Human pathology in NCL.

In childhood the neuronal ceroid lipofuscinoses (NCL) are the most frequent lysosomal diseases and the most frequent neurodegenerative diseases but, in adulthood, they represent a small fraction among the neurodegenerative diseases. Their morphology is marked by: (i) loss of neurons, foremost in the cerebral and cerebellar cortices resulting in cerebral and cerebellar atrophy; (ii) an almost ubiquitous accumulation of lipopigments in nerve cells, but also in extracerebral tissues. Loss of cortical neurons is selective, indiscriminate depletion in early childhood forms occurring only at an advanced stage, whereas loss of neurons in subcortical grey-matter regions has not been quantitatively documented. Among the fourteen different forms of NCL described to date, CLN1 and CLN10 are marked by granular lipopigments, CLN2 by curvilinear profiles (CVPs), CLN3 by fingerprint profiles (FPPs), and other forms by a combination of these features. Among extracerebral tissues, lymphocytes, skin, rectum, skeletal muscle and, occasionally, conjunctiva are possible guiding targets for diagnostic identification, the precise type of NCL then requiring molecular analysis within the clinical and morphological context. Autosomal-recessive adult NCL has been linked molecularly to different childhood forms, i.e. CLN1, CLN5, and CLN6, whilst autosomal-dominant adult NCL, now designated as CLN4, is caused by a newly identified separate gene, DNAJC5. This article is part of a Special Issue entitled: The Neuronal Ceroid Lipofuscinoses or Batten Disease.

CLN8 Mutations Presenting with a Phenotypic Continuum of Neuronal Ceroid Lipofuscinosis-Literature Review and Case Report.

CLN8 is a ubiquitously expressed membrane-spanning protein that localizes primarily in the ER, with partial localization in the ER-Golgi intermediate compartment. Mutations in CLN8 cause late-infantile neuronal ceroid lipofuscinosis (LINCL). We describe a female pediatric patient with LINCL. She exhibited a typical phenotype associated with LINCL, except she did not present spontaneous myoclonus, her symptoms occurrence was slower and developed focal sensory visual seizures. In addition, whole-exome sequencing identified a novel homozygous variant in CLN8, c.531G>T, resulting in p.Trp177Cys. Ultrastructural examination featured abundant lipofuscin deposits within mucosal cells, macrophages, and monocytes. We report a novel CLN8 mutation as a cause for NCL8 in a girl with developmental delay and epilepsy, cerebellar syndrome, visual loss, and progressive cognitive and motor regression. This case, together with an analysis of the available literature, emphasizes the existence of a continuous spectrum of CLN8-associated phenotypes rather than a sharp distinction between them.

Moyamoya and progressive myoclonic epilepsy secondary to CLN6 bi-allelic mutations - A previously unreported association.

The neuronal ceroid lipofuscinoses (NCL) are a collection of lysosomal storage diseases characterised by the accumulation of characteristic inclusions containing lipofuscin in various tissues of the body and are one of the causes of progressive myoclonic epilepsy. Mutations in at least thirteen genes have been identified as causes of NCL, which can present as infantile, late-infantile, juvenile or adult forms. CLN6 codes for an endoplasmic reticulum transmembrane protein of unknown function. Homozygous and compound heterozygous mutations of the gene are associated with both late-infantile (LINCL) and adult onset (ANCL) forms of NCL, including Kufs disease, comprising ANCL without associated visual loss. Moyamoya, a rare vasculopathy of the circle of Willis, has been reported in conjunction with a number of inflammatory and other diseases, as well as a handful of lysosomal storage diseases. To our knowledge, this is the first reported case of Moyamoya in the context of the neuronal ceroid lipofuscinoses or a CLN6-related disease.

Neural stem cells for disease modeling and evaluation of therapeutics for infantile (CLN1/PPT1) and late infantile (CLN2/TPP1) neuronal ceroid lipofuscinoses.

BACKGROUND: Infantile and late infantile neuronal ceroid lipofuscinoses (NCLs) are lysosomal storage diseases affecting the central nervous system (CNS). The infantile NCL (INCL) is caused by mutations in the PPT1 gene and late-infantile NCL (LINCL) is due to mutations in the TPP1 gene. Deficiency in PPT1 or TPP1 enzyme function results in lysosomal accumulation of pathological lipofuscin-like material in the patient cells. There is currently no small-molecular drug treatment for NCLs. RESULTS: We have generated induced pluripotent stem cells (iPSC) from three patient dermal fibroblast lines and further differentiated them into neural stem cells (NSCs). Using these new disease models, we evaluated the effect of δ-tocopherol (DT) and hydroxypropyl-ß-cyclodextrin (HPBCD) with the enzyme replacement therapy as the control. Treatment with the relevant recombinant enzyme or DT significantly ameliorated the lipid accumulation and lysosomal enlargement in the disease cells. A combination therapy of δ-tocopherol and HPBCD further improved the effect compared to that of either drug used as a single therapy. CONCLUSION: The results demonstrate that these patient iPSC derived NCL NSCs are valid cell- based disease models with characteristic disease phenotypes that can be used for study of disease pathophysiology and drug development.