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The Journal of Neuroscience, February 21, 2007, 27(8):2081-2090; doi:10.1523/JNEUROSCI.5577-06.2007

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Neurobiology of Disease
Cathepsin D Deficiency Induces Persistent Neurodegeneration in the Absence of Bax-Dependent Apoptosis

John J. Shacka,¹ Barbara J. Klocke,¹ Chainllie Young,² Masahiro Shibata,³ John W. Olney,² Yasuo Uchiyama,³ Paul Saftig,⁴ and Kevin A. Roth¹

¹Department of Pathology, Neuropathology Division, University of Alabama at Birmingham, Birmingham, Alabama 35294, ²Department of Psychiatry, Washington University School of Medicine, St. Louis, Missouri 63110, ³Department of Cell Biology and Neurosciences, Osaka University Graduate School of Medicine, Suita, Osaka 565-0871, Japan, and ⁴Department of Biochemistry, University Kiel, D-24098 Kiel, Germany

Correspondence should be addressed to Dr. Kevin A. Roth, Department of Pathology, Neuropathology Division, University of Alabama at Birmingham, SC 961 1530 3rd Avenue South, Birmingham, AL 35294-0017. Email: karoth{at}uab.edu

Neuronal ceroid lipofuscinosces/Batten disease (NCL) is a devastating group of neurodegenerative diseases caused by genetic disruptions in lysosomal function. Cathepsin D (CD) is a major lysosomal protease, and mutations in CD that render it enzymatically defective have been reported recently in subsets of NCL patients. The targeted deletion of CD in mice results in extensive neuropathology, including biochemical and morphological evidence of apoptosis and autophagic stress (aberrant autophagosome accumulation), effects that are similar to those observed in NCL. To determine the contribution of Bax-dependent apoptosis in this mouse model of NCL, combined Bax- and CD-deficient mice were generated. Morphological analysis of CD-deficient mouse brains indicated large numbers of pyknotic neurons and neurons with marked cytoplasmic swellings containing undigested lipofuscin. Cell death and apoptosis were evidenced by increases in terminal deoxynucleotidyl transferase-mediated biotinylated UTP nick end labeling (TUNEL) reactivity and activation of caspase-3, respectively. DeOlmos silver-positive neurons were abundant in CD-deficient brain and correlated with neuron loss, as indicated by significant decreases in NeuN (neuronal nuclear antigen)-positive neurons. Lysosome dysfunction and autophagic stress were apparent in CD-deficient brain as indicated by the accumulation of autofluorescent storage material and by increased levels of LC3-II (light chain 3-II, a selective autophagosome marker), respectively. Bax deletion significantly inhibited caspase-3 activation and hippocampal TUNEL reactivity but did not prevent the majority of CD deficiency-induced neuropathology, including the persistence of pyknotic neurons, elevated cortical TUNEL reactivity, lysosome dysfunction and autophagic stress, neurodegeneration, and neuron loss. Together, these results suggest that CD deficiency-induced neuropathology does not require Bax-dependent apoptosis and highlights the importance of caspase-independent neuron death and neurodegeneration resulting from the genetic disruption of lysosome function.

Key words: apoptosis; autophagic stress; autophagy; cathepsin D; Bax; neurodegeneration

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Received Aug. 18, 2006; revised Jan. 17, 2007; accepted Jan. 20, 2007.

Correspondence should be addressed to Dr. Kevin A. Roth, Department of Pathology, Neuropathology Division, University of Alabama at Birmingham, SC 961 1530 3rd Avenue South, Birmingham, AL 35294-0017. Email: karoth{at}uab.edu

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