Motor Neuron-specific Disruption of Proteasomes, but Not Autophagy, Replicates Amyotrophic Lateral Sclerosis
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.
Available from: Jianhua Xiong
- "Lean body mass and acquisition of brown adipose tissue features Zhang et al., 2009a; Singh et al., 2009b Mammary gland WAP-Cre Impaired keratin 8 homeostasis; defective phagocytosis and enhanced inflammatory responses Kongara et al., 2010; Teplova et al., 2013 Neuron Nestin-Cre Neurodegenerative symptoms Komatsu et al., 2006a Pcp2-Cre Axonal dystrophy Komatsu et al., 2007 POMC-Cre Elevated lipolysis; dysregulation of metabolic modulation Kaushik et al., 2012; Coupe et al., 2012 CamKII-Cre Neurodegenerative symptoms Inoue et al., 2012a; Nilsson et al., 2013 Cre- expressing viruses Aberrant inflammation responses; repressed retrograde degeneration of dopaminergic axons Cheng et al., 2011; Motori et al., 2013 VAChT-Cre No apparent phenotypes of amyotrophic lateral sclerosis Tashiro et al., 2012 DAT-Cre Neurodegenerative symptoms; altered dopaminergic axonal profile and morphology Inoue et al., 2012a; Hernandez et al., 2012 Function of Atg7 "
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ABSTRACT: Macroautophagy is an evolutionarily conserved intracellular degradation system used by life ranging from yeasts to mammals. The core autophagic machinery is composed of ATG (autophagy-related) protein constituents. One particular member of the ATG protein family, Atg7, has been the focus of recent research. Atg7 acts as an E1-like activating enzyme facilitating both microtubule-associated protein light chain 3 (LC3)-phosphatidylethanolamine and ATG12 conjugation. Thus, Atg7 stands at the hub of these two ubiquitin-like systems involving LC3 and Atg12 in autophagic vesicle expansion. In this review, I focus on the pleiotropic function of Atg7 in development, maintenance of health, and alternations of such control in disease.
Available from: Shengzhou Wu
- "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.
Available from: Eric A Reits
- "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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ABSTRACT: The ubiquitin proteasome system (UPS) is crucial for intracellular protein homeostasis and for degradation of aberrant and damaged proteins. The accumulation of ubiquitinated proteins is a hallmark of many neurodegenerative diseases, including amyotrophic lateral sclerosis, Alzheimer's, Parkinson's, and Huntington's disease, leading to the hypothesis that proteasomal impairment is contributing to these diseases. So far, most research related to the UPS in neurodegenerative diseases has been focused on neurons, while glial cells have been largely disregarded in this respect. However, glial cells are essential for proper neuronal function and adopt a reactive phenotype in neurodegenerative diseases, thereby contributing to an inflammatory response. This process is called reactive gliosis, which in turn affects UPS function in glial cells. In many neurodegenerative diseases, mostly neurons show accumulation and aggregation of ubiquitinated proteins, suggesting that glial cells may be better equipped to maintain proper protein homeostasis. During an inflammatory reaction, the immunoproteasome is induced in glia, which may contribute to a more efficient degradation of disease-related proteins. Here we review the role of the UPS in glial cells in various neurodegenerative diseases, and we discuss how studying glial cell function might provide essential information in unraveling mechanisms of neurodegenerative diseases.
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