Cerebellar Pathology and Motor Deficits in the Palmitoyl Protein Thioesterase 1-deficient Mouse

Overview

Journal Exp Neurol

Specialty Neurology

Date 2009 May 7

PMID 19416667

Citations 46

Authors

Shannon L Macauley

David F Wozniak

Catherine Kielar

Yun Tan

Jonathan D Cooper

Mark S Sands

Affiliations

Soon will be listed here.

Abstract

Infantile neuronal ceroid lipofuscinosis (INCL, Infantile Batten Disease) is an inherited, neurodegenerative lysosomal storage disorder. INCL is the result of a CLN1 gene mutation leading to a deficiency in palmitoyl protein thioesterase 1 (PPT1) activity. Studies in the forebrain demonstrate the PPT1-deficient mouse (PPT1-/-) mimics the clinical symptoms and underlying pathology of INCL; however, little is known about changes in cerebellar function or pathology. In this study, we demonstrate Purkinje cell loss beginning at 3 months, which correlates with changes in rotarod performance. Concurrently, we observed an early stage reactive gliosis and a primary pathology in astrocytes, including changes in S100beta and GLAST expression. Conversely, there was a late stage granule cell loss, microglial activation, and demyelination. This study suggests that neuronal-glial interactions are the core pathology in the PPT1-/- cerebellum. In addition, these data identify potential endpoints for use in future efficacy studies for the treatment of INCL.

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References

Haltia M, Rapola J, Santavuori P, Keranen A . Infantile type of so-called neuronal ceroid-lipofuscinosis. 2. Morphological and biochemical studies. J Neurol Sci. 1973; 18(3):269-85. DOI: 10.1016/0022-510x(73)90076-2. View

Haltia M . The neuronal ceroid-lipofuscinoses. J Neuropathol Exp Neurol. 2003; 62(1):1-13. DOI: 10.1093/jnen/62.1.1. View

Armstrong C, Krueger-Naug A, Currie R, Hawkes R . Constitutive expression of heat shock protein HSP25 in the central nervous system of the developing and adult mouse. J Comp Neurol. 2001; 434(3):262-74. DOI: 10.1002/cne.1176. View

Kohlschutter A, Gardiner R, Goebel H . Human forms of neuronal ceroid-lipofuscinosis (Batten disease): consensus on diagnostic criteria, Hamburg 1992. J Inherit Metab Dis. 1993; 16(2):241-4. DOI: 10.1007/BF00710254. View

Taupin P . HuCNS-SC (StemCells). Curr Opin Mol Ther. 2006; 8(2):156-63. View

Vanhanen S, Sainio K, Lappi M, Santavuori P . EEG and evoked potentials in infantile neuronal ceroid-lipofuscinosis. Dev Med Child Neurol. 1997; 39(7):456-63. DOI: 10.1111/j.1469-8749.1997.tb07465.x. View

Wainwright M, Craft J, Griffin W, Marks A, Pineda J, Padgett K . Increased susceptibility of S100B transgenic mice to perinatal hypoxia-ischemia. Ann Neurol. 2004; 56(1):61-7. DOI: 10.1002/ana.20142. View

Kielar C, Maddox L, Bible E, Pontikis C, Macauley S, Griffey M . Successive neuron loss in the thalamus and cortex in a mouse model of infantile neuronal ceroid lipofuscinosis. Neurobiol Dis. 2006; 25(1):150-62. PMC: 1866219. DOI: 10.1016/j.nbd.2006.09.001. View

Sarna J, Miranda S, Schuchman E, Hawkes R . Patterned cerebellar Purkinje cell death in a transgenic mouse model of Niemann Pick type A/B disease. Eur J Neurosci. 2001; 13(10):1873-80. DOI: 10.1046/j.0953-816x.2001.01564.x. View

10.

Armstrong C, Krueger-Naug A, Currie R, Hawkes R . Constitutive expression of the 25-kDa heat shock protein Hsp25 reveals novel parasagittal bands of purkinje cells in the adult mouse cerebellar cortex. J Comp Neurol. 1999; 416(3):383-97. DOI: 10.1002/(sici)1096-9861(20000117)416:3<383::aid-cne9>3.0.co;2-m. View

11.

Hofmann S, Das A, Lu J, Soyombo A . Positional candidate gene cloning of CLN1. Adv Genet. 2001; 45:69-92. DOI: 10.1016/s0065-2660(01)45004-8. View

12.

Haltia M, Rapola J, Santavuori P . Infantile type of so-called neuronal ceroid-lipofuscinosis. Histological and electron microscopic studies. Acta Neuropathol. 1973; 26(2):157-70. DOI: 10.1007/BF00697751. View

13.

Mole S, Williams R, Goebel H . Correlations between genotype, ultrastructural morphology and clinical phenotype in the neuronal ceroid lipofuscinoses. Neurogenetics. 2005; 6(3):107-26. DOI: 10.1007/s10048-005-0218-3. View

14.

Sarna J, Hawkes R . Patterned Purkinje cell death in the cerebellum. Prog Neurobiol. 2003; 70(6):473-507. DOI: 10.1016/s0301-0082(03)00114-x. View

15.

Santavuori P, Haltia M, Rapola J . Infantile type of so-called neuronal ceroid-lipofuscinosis. Dev Med Child Neurol. 1974; 16(5):644-53. DOI: 10.1111/j.1469-8749.1974.tb04183.x. View

16.

Rothermundt M, Peters M, Prehn J, Arolt V . S100B in brain damage and neurodegeneration. Microsc Res Tech. 2003; 60(6):614-32. DOI: 10.1002/jemt.10303. View

17.

Griffey M, Bible E, Vogler C, Levy B, Gupta P, Cooper J . Adeno-associated virus 2-mediated gene therapy decreases autofluorescent storage material and increases brain mass in a murine model of infantile neuronal ceroid lipofuscinosis. Neurobiol Dis. 2004; 16(2):360-9. DOI: 10.1016/j.nbd.2004.03.005. View

18.

Chang M, Cooper J, Sleat D, Cheng S, Dodge J, Passini M . Intraventricular enzyme replacement improves disease phenotypes in a mouse model of late infantile neuronal ceroid lipofuscinosis. Mol Ther. 2008; 16(4):649-56. DOI: 10.1038/mt.2008.9. View

19.

Gupta P, Soyombo A, Atashband A, Wisniewski K, Shelton J, Richardson J . Disruption of PPT1 or PPT2 causes neuronal ceroid lipofuscinosis in knockout mice. Proc Natl Acad Sci U S A. 2001; 98(24):13566-71. PMC: 61081. DOI: 10.1073/pnas.251485198. View

20.

Galvin N, Vogler C, Levy B, Kovacs A, Griffey M, Sands M . A murine model of infantile neuronal ceroid lipofuscinosis-ultrastructural evaluation of storage in the central nervous system and viscera. Pediatr Dev Pathol. 2007; 11(3):185-92. PMC: 2789460. DOI: 10.2350/07-03-0242.1. View