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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