Disruption of PPT1 or PPT2 causes neuronal ceroid lipofuscinosis in knockout mice

Praveena Gupta, Abigail A. Soyombo, Armita Atashband, Krystyna E. Wisniewski, John M. Shelton, James A. Richardson, Robert E. Hammer, Sandra L. Hofmann

Research output: Contribution to journalArticle

191 Citations (Scopus)

Abstract

PPT1 and PPT2 encode two lysosomal thioesterases that catalyze the hydrolysis of long chain fatty acyl CoAs. In addition to this function, PPT1 (palmitoyl-protein thioesterase 1) hydrolyzes fatty acids from modified cysteine residues in proteins that are undergoing degradation in the lysosome. PPT1 deficiency in humans causes a neurodegenerative disorder, infantile neuronal ceroid lipofuscinosis (also known as infantile Batten disease). In the current work, we engineered disruptions in the PPT1 and PPT2 genes to create "knockout" mice that were deficient in either enzyme. Both lines of mice were viable and fertile. However, both lines developed spasticity (a "clasping" phenotype) at a median age of 21 wk and 29 wk, respectively. Motor abnormalities progressed in the PPT1 knockout mice, leading to death by 10 mo of age. In contrast, the majority of PPT2 mice were alive at 12 mo. Myoclonic jerking and seizures were prominent in the PPT1 mice. Autofluorescent storage material was striking throughout the brains of both strains of mice. Neuronal loss and apoptosis were particularly prominent in PPT1-deficient brains. These studies provide a mouse model for infantile neuronal ceroid lipofuscinosis and further suggest that PPT2 serves a role in the brain that is not carried out by PPT1.

Original languageEnglish (US)
Pages (from-to)13566-13571
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume98
Issue number24
DOIs
StatePublished - Nov 20 2001
Externally publishedYes

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Neuronal Ceroid-Lipofuscinoses
Knockout Mice
Brain
Myoclonus
palmitoyl-protein thioesterase
Lysosomes
Neurodegenerative Diseases
Proteolysis
Cysteine
Seizures
Hydrolysis
Fatty Acids
Apoptosis
Phenotype

ASJC Scopus subject areas

  • Genetics
  • General

Cite this

Gupta, P., Soyombo, A. A., Atashband, A., Wisniewski, K. E., Shelton, J. M., Richardson, J. A., ... Hofmann, S. L. (2001). Disruption of PPT1 or PPT2 causes neuronal ceroid lipofuscinosis in knockout mice. Proceedings of the National Academy of Sciences of the United States of America, 98(24), 13566-13571. https://doi.org/10.1073/pnas.251485198

Disruption of PPT1 or PPT2 causes neuronal ceroid lipofuscinosis in knockout mice. / Gupta, Praveena; Soyombo, Abigail A.; Atashband, Armita; Wisniewski, Krystyna E.; Shelton, John M.; Richardson, James A.; Hammer, Robert E.; Hofmann, Sandra L.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 98, No. 24, 20.11.2001, p. 13566-13571.

Research output: Contribution to journalArticle

Gupta, P, Soyombo, AA, Atashband, A, Wisniewski, KE, Shelton, JM, Richardson, JA, Hammer, RE & Hofmann, SL 2001, 'Disruption of PPT1 or PPT2 causes neuronal ceroid lipofuscinosis in knockout mice', Proceedings of the National Academy of Sciences of the United States of America, vol. 98, no. 24, pp. 13566-13571. https://doi.org/10.1073/pnas.251485198
Gupta, Praveena ; Soyombo, Abigail A. ; Atashband, Armita ; Wisniewski, Krystyna E. ; Shelton, John M. ; Richardson, James A. ; Hammer, Robert E. ; Hofmann, Sandra L. / Disruption of PPT1 or PPT2 causes neuronal ceroid lipofuscinosis in knockout mice. In: Proceedings of the National Academy of Sciences of the United States of America. 2001 ; Vol. 98, No. 24. pp. 13566-13571.
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