Autophagy manages disease-associated stress granules

Abnormal accumulation of cytosolic aggregates or inclusion bodies is a hallmark of several neurodegenerative diseases. Many common or specific molecular components such as ubiquitin, α-synuclein, TDP-43, or tau in neuronal cytosolic inclusion bodies have been identified as being associated with cellular pathogenic mechanisms of disease. Recently, stress granule (SG) marker proteins such as PABP and G3BP were found in cytosolic inclusion bodies of patients with frontotemporal lobar dementia (FTLD), alzheimer's disease (AD), or amyotrophic lateral sclerosis (ALS), suggesting that inappropriate SG dynamics contribute to pathogenic mechanisms [1]. Moreover, disease-associated tau, ataxin-2, survival of motor neurons (SMN), and angiogenin (ANG) proteins are recruited to SGs under stress conditions, and mutations in FMRP or hnRNPA1 are known to cause severe impairment of SG dynamics. Collectively, these facts suggest a common possible role for SG dysregulation in neurodegeneration. In detail, SGs are dense aggregates composed of RNA-binding proteins and non-translating mRNAs that are rapidly assembled upon stress exposure to inhibit improper mRNA translation and cell death and then disassembled thereafter [2]. Therefore, fine regulation of SG dynamics and homeostasis is very important for the stress response and cell survival, especially in non-dividing cells such as neurons. Despite prior studies on dynamics of SGs, regulatory mechanisms of disease-associated SGs in the context of neuronal degradation as well as the roles of persistent SGs in neurodegeneration are largely unknown. To address these questions, our study investigated the role of autophagy, which controls the quality of proteins or organelles, in the regulation of ALS-linked SGs and neurodegeneration in disease-associated cultured neurons [3]. Fused in sarcoma (FUS), which was initially identified as a fusion oncogene, is a multifunctional RNA-binding protein whose mutations have been detected in ALS and FTLD [4]. In our study, ALS-linked FUS (R521C) mutation caused persistent SG accumulation upon oxidative stress, likely due to impairment of FUS disassembly from SGs, which is consistent with other cellular studies on FUS mutations [5]. Interestingly, mutant FUS-positive SGs showed greater accumulation in autophagosomes due to reduced autophagic flux compared to wild-type FUS-positive SGs, thereby supporting an active role for autophagy in regulation of SGs in neurons. Moreover, we directly confirmed autophagic regulation of physiological SGs in neurons based on our observation that inhibition of autophagy using atg7 siRNA increased the number of SGs, whereas activation of autophagy reduced SG accumulation. Further analysis showed that mutant FUS-positive SGs were regulated by autophagy regulation in post-mitotic neurons. Most importantly, …