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Decreased sensitivity of palmitoyl protein thioesterase 1-deficient neurons to chemical anoxia

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Abstract

Infantile CLN1 disease, also known as infantile neuronal ceroid lipofuscinosis, is a fatal childhood neurodegenerative disorder caused by mutations in the CLN1 gene. CLN1 encodes a soluble lysosomal enzyme, palmitoyl protein thioesterase 1 (PPT1), and it is still unclear why neurons are selectively vulnerable to the loss of PPT1 enzyme activity in infantile CLN1 disease. To examine the effects of PPT1 deficiency on several well-defined neuronal signaling and cell death pathways, different toxic insults were applied in cerebellar granule neuron cultures prepared from wild type (WT) and palmitoyl protein thioesterase 1-deficient (Ppt1 −/−) mice, a model of infantile CLN1 disease. Glutamate uptake inhibition by t-PDC (L-trans-pyrrolidine-2,4-dicarboxylic acid) or Zn2+-induced general mitochondrial dysfunction caused similar toxicity in WT and Ppt1 −/− cultures. Ppt1 −/− neurons, however, were more sensitive to mitochondrial complex I inhibition by MPP+ (1-methyl-4-phenylpyridinium), and had significantly decreased sensitivity to chemical anoxia induced by the mitochondrial complex IV inhibitor, sodium azide. Our results indicate that PPT1 deficiency causes alterations in the mitochondrial respiratory chain.

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Fig. 1

Abbreviations

AMPA:

α-amino-3-hydroxy-5-methyl-4-isoxazolepropionate

DIV:

Day in vitro

MPP+ :

1-methyl-4-phenylpyridinium

MTT:

3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide

NCLs:

Neuronal ceroid lipofuscinoses

NOS:

Nitric oxide synthase

NMDA:

N-methyl-D-aspartate

PPT1:

Palmitoyl protein thioesterase 1

ROS:

Reactive oxygen species

t-PDC:

L-trans-pyrrolidine-2,4-dicarboxylic acid

WT:

Wild type

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Acknowledgments

This work was supported in part by Hayden’s Hope and the National Institutes of Health (NS044310, NS067147).

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Authors and Affiliations

  1. Sanford Children’s Health Research Center, Sanford Research, 2301 E. 60th Street, Sioux Falls, SD, 57104, USA

    Meredith Meyer, Attila D. Kovács & David A. Pearce

  2. Department of Pediatrics, Sanford School of Medicine, University of South Dakota Sioux Falls, Sioux Falls, SD, 57104, USA

    Attila D. Kovács & David A. Pearce

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  1. Meredith Meyer
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  2. Attila D. Kovács
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  3. David A. Pearce
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Correspondence to David A. Pearce.

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Meyer, M., Kovács, A.D. & Pearce, D.A. Decreased sensitivity of palmitoyl protein thioesterase 1-deficient neurons to chemical anoxia. Metab Brain Dis 32, 275–279 (2017). https://doi.org/10.1007/s11011-016-9919-6

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