Characterizing pathogenic processes in Batten disease: Use of small eukaryotic model systems

Center for Aging and Developmental Biology, Aab Institute of Biomedical Science, University of Rochester School of Medicine and Dentistry, Rochester, NY 14642, USA.
Biochimica et Biophysica Acta (Impact Factor: 4.66). 11/2006; 1762(10):906-19. DOI: 10.1016/j.bbadis.2006.08.010
Source: PubMed


The neuronal ceroid lipofuscinoses (NCLs) are neurodegenerative disorders. Nevertheless, small model organisms, including those lacking a nervous system, have proven invaluable in the study of mechanisms that underlie the disease and in studying the functions of the conserved proteins associated to each disease. From the single-celled yeast, Saccharomyces cerevisiae and Schizosaccharomyces pombe, to the worm, Caenorhabditis elegans and the fruitfly, Drosophila melanogaster, biochemical and, in particular, genetic studies on these organisms have provided insight into the NCLs.

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    • "Eight genes are linked to childhood-onset NCL, but many late-onset clinical forms as well as some pediatric forms remain without identified genetic etiologies. Studies using lower mammal and other eukaryotic disease models suggest that lipid and protein trafficking defects in the endocytic and lysosomal systems underlie NCL disease biology (reviewed in [2-4]). "
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    ABSTRACT: The neuronal ceroid lipofuscinoses (NCLs, or Batten disease) comprise the most common Mendelian form of childhood-onset neurodegeneration, but the functions of the known underlying gene products remain poorly understood. The clinical heterogeneity of these disorders may shed light on genetic interactors that modify disease onset and progression. We describe a proband with congenital hypotonia and an atypical form of infantile-onset, biopsy-proven NCL. Pathologic and molecular work-up of this patient identified CLN5 mutations as well as a mutation-previously described as incompletely penetrant or a variant of unknown significance-in POLG1, a nuclear gene essential for maintenance of mitochondrial DNA (mtDNA) copy number. The congenital presentation of this patient is far earlier than that described for either CLN5 patients or affected carriers of the POLG1 variant (c.1550 G > T, p.Gly517Val). Assessment of relative mtDNA copy number and mitochondrial membrane potential in the proband and control subjects suggested a pathogenic effect of the POLG1 change as well as a possible functional interaction with CLN5 mutations. These findings suggest that an incompletely penetrant variant in POLG1 may modify the clinical phenotype in a case of CLN5 and are consistent with emerging evidence of interactions between NCL-related genes and mitochondrial physiology.
    BMC Medical Genetics 06/2012; 13(1):50. DOI:10.1186/1471-2350-13-50 · 2.08 Impact Factor
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    • "The precise function of the NCL proteins as well as the disease mechanisms is largely unknown. The advancement in cell biological and genome-wide analyses [13] [16] as well as development of various model organisms [17] [18] has produced a vast amount of data for NCL biology and these achievements are summarized in this review. "
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    ABSTRACT: The neuronal ceroid lipofuscinoses (NCL) are severe neurodegenerative lysosomal storage disorders of childhood, characterized by accumulation of autofluorescent ceroid lipopigments in most cells. NCLs are caused by mutations in at least ten recessively inherited human genes, eight of which have been characterized. The NCL genes encode soluble and transmembrane proteins, localized to the endoplasmic reticulum (ER) or the endosomal/lysosomal organelles. The precise function of most of the NCL proteins has remained elusive, although they are anticipated to carry pivotal roles in the central nervous system. Common clinical features in NCL, including retinopathy, motor abnormalities, epilepsia and dementia, also suggest that the proteins may be functionally linked. All subtypes of NCLs present with selective neurodegeneration in the cerebral and cerebellar cortices. Animal models have provided valuable data about the pathological characteristics of NCL and revealed that early glial activation precedes neuron loss in the thalamocortical system. The mouse models have also been efficiently utilized for the evaluation of therapeutic strategies. The tools generated by the accomplishments in genomics have further substantiated global analyses and these have initially provided new insights into the NCL field. This review summarizes the current knowledge of the NCL proteins, basic characteristics of each disease and studies of pathogenetic mechanisms in animal models of these diseases.
    Biochimica et Biophysica Acta 12/2008; 1793(4):697-709. DOI:10.1016/j.bbamcr.2008.11.004 · 4.66 Impact Factor
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    ABSTRACT: The most common neurodegenerative genetic childhood disease, juvenile neuronal ceroid lipofuscinosis (JNCL), is a lysosomal storage disorder that is caused by mutations in the CLN3 gene. In patients' lysosomes material accumulates primarily composed of Subunit c. How mutations in CLN3 lead to this disease is unknown. The nematode Caenorhabditis elegans is useful for researching genetic neurodegenerative diseases. C. elegans has three CLN3 homologous proteins, cln-3.1, cln-3.2, and cln-3.3. Nematode cln-3 mutants were generated, crossed to obtain double and triple mutants, and their phenotypes were studied. Cln-3 triple mutants have slightly decreased life span and little decreased brood size. This triple mutant is viable, indicating that cln-3 genes are not essential for nematode life under laboratory conditions. These phenotypes are not useable in genetic screens and no neurological or other robust phenotypes were present. Expression analysis was performed to focus the phenotypic analysis. The short life span of C. elegans may explain the lack of accumulated materials. Therefore, Subunit c was inducibly overexpressed in cln-3 triple mutants. This is deleterious to nematodes, appearing to affect mitochondrial ultrastructure, although similar in wildtype and cln-3 mutants. Additional experiments with this nematode model may increase our understanding of the function of the cln-3 genes.
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