Motor Neuron-specific Disruption of Proteasomes, but Not Autophagy, Replicates Amyotrophic Lateral Sclerosis

Kyoto University Graduate School of Medicine, Japan
Journal of Biological Chemistry (Impact Factor: 4.57). 10/2012; 287(51). DOI: 10.1074/jbc.M112.417600
Source: PubMed


Evidence suggests that protein misfolding is crucially involved in the pathogenesis of amyotrophic lateral sclerosis (ALS). However, controversy still exists regarding the involvement of proteasomes or autophagy in ALS due to previous conflicting results. Here, we show that impairment of the ubiquitin-proteasome system, but not the autophagy-lysosome system in motor neurons replicates ALS in mice. Conditional knockout mice of the proteasome subunit Rpt3 in a motor neuron-specific manner (Rpt3-CKO) showed locomotor dysfunction accompanied by progressive motor neuron loss and gliosis. Moreover, diverse ALS-linked proteins, including TAR DNA binding protein 43 kDa (TDP-43), fused in sarcoma (FUS), ubiquilin 2, and optineurin were mislocalized or accumulated in motor neurons, together with other typical ALS hallmarks such as basophilic inclusion bodies. On the other hand, motor neuron-specific knockout of Atg7, a crucial component for the induction of autophagy (Atg7-CKO), only resulted in cytosolic accumulation of ubiquitin and p62, and no TDP-43 or FUS pathologies or motor dysfunction was observed. These results strongly suggest that proteasomes, but not autophagy, fundamentally govern the development of ALS in which TDP-43 and FUS proteinopathy may play a crucial role. Enhancement of proteasome activity may be a promising strategy for the treatment of ALS.

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    • "Reports have shown that proteasome activity is decreased in the substantia nigra in PD (McNaught and Jenner, 2001; McNaught et al., 2003) and in affected brain regions in AD (Keller et al., 2000a). Conditional knockout of a proteasome subunit reproduces aspects of ALS in mice (Tashiro et al., 2012). Endoplasmic reticulum (ER) is responsible for many important functions, including protein synthesis, posttranslational modifications, protein quality control, calcium storage, and intracellular signaling. "
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    ABSTRACT: Evidence indicates that the ubiquitin-proteasome system and the endoplasmic retculum (ER) quality-control system work in concert to ensure that proteins are correctly folded in the ER and that misfolded proteins are retrotransported to the cytosol for degradation by proteasomes. Dysfunction of either system results in developmental abnormalities and even death in animals. This study investigates whether and how proteasome inhibition impacts the components of the calreticulin (CRT)/calnexin (CNX) glycoprotein folding machinery, a typical ER protein quality-control system, in the context of early neuronal injury. Here we report that proteasome inhibitor treatments, at nonlethal levels, reduced protein levels of CRT and ERp57 but not of CNX. These treatments increased protein levels of CRT in culture media, an effect blocked by brefeldin A, an inhibitor of protein trafficking; by contrast, ERp57 was not detected in culture media. Knockdown of CRT levels alone increased the vulnerability of SH-SY5Y, a neuronal cell line, to 6-hydroxydopamine (6-OHDA) toxicity. In a rat model of Parkinson's disease, intrastriatal 6-OHDA lesions resulted in decreased levels of CRT and ERp57 in the midbrain. These findings suggest that reduction of the components of CRT/CNX glycoprotein quality-control system may play a role in neuronal injury in Parkinson's disease and other neurodegenerative disorders associated with dysfunction of the ubiquitin-proteasome system. © 2014 Wiley Periodicals, Inc.
    Full-text · Article · Oct 2014 · Journal of Neuroscience Research
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    • "In the brain, disturbances in either of the two cause the accumulation and aggregation of short-lived and misfolded proteins. In aging neurons, UPS activity has been shown to be decreased (Tydlacka et al., 2008), accordingly, age-related alterations in proteasomal activity are implicated in various neurodegenerative diseases (Tydlacka et al., 2008; Tashiro et al., 2012; Lin et al., 2013; Orre et al., 2013). It remains to be examined in more detail whether and how proteasome levels and activity differ between neurons and glia, which would obviously affect the capacity of cells to maintain proper protein homeostasis. "
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