Loss of autophagy in the central nervous system causes neurodegeneration in mice

Abstract

Protein quality-control, especially the removal of proteins with aberrant structures, has an important role in maintaining the homeostasis of non-dividing neural cells. In addition to the ubiquitin-proteasome system, emerging evidence points to the importance of autophagy--the bulk protein degradation pathway involved in starvation-induced and constitutive protein turnover--in the protein quality-control process. However, little is known about the precise roles of autophagy in neurons. Here we report that loss of Atg7 (autophagy-related 7), a gene essential for autophagy, leads to neurodegeneration. We found that mice lacking Atg7 specifically in the central nervous system showed behavioural defects, including abnormal limb-clasping reflexes and a reduction in coordinated movement, and died within 28 weeks of birth. Atg7 deficiency caused massive neuronal loss in the cerebral and cerebellar cortices. Notably, polyubiquitinated proteins accumulated in autophagy-deficient neurons as inclusion bodies, which increased in size and number with ageing. There was, however, no obvious alteration in proteasome function. Our results indicate that autophagy is essential for the survival of neural cells, and that impairment of autophagy is implicated in the pathogenesis of neurodegenerative disorders involving ubiquitin-containing inclusion bodies.

Long live FOXO: unraveling the role of FOXO proteins in aging and longevity

“…In fact, it has been shown that FOXO factors participate in the regulation of genes responsible for two main mechanisms of intracellular clearance: autophagy and the ubiquitin‐proteasome system (Webb & Brunet, 2014). Defects in autophagy, the process of degradation and recycling of cytoplasmic proteins and organelles in response to starvation have been associated with premature aging and age‐related disorders (Hara et al ., 2006; Komatsu et al ., 2006; Jung et al ., 2008; Pickford et al ., 2008; Masiero et al ., 2009; Lee et al ., 2010a, 2010b). FOXOs affect the expression of genes involved in autophagy and mitophagy (muscle‐specific autophagy) in muscle cells from flies (dFOXO) to mammals (FOXO3), allowing adaptation of the tissues to starvation (Zhao et al ., 2007; Sengupta et al ., 2009; Demontis & Perrimon, 2010).…”

“…The mechanism(s) by which Foxo factors contribute to lifespan remain elusive. As previously mentioned, decreased autophagy has been related to premature aging and age‐related associated disorders (Hara et al ., 2006; Komatsu et al ., 2006; Jung et al ., 2008; Pickford et al ., 2008; Masiero et al ., 2009; Lee et al ., 2010a, 2010b). Foxo factors have been shown to regulate autophagy in mouse muscle, particularly Foxo3, which induces the expression of several autophagy genes and increases autophagosome formation (Mammucari et al ., 2007; Zhao et al ., 2007; Webb & Brunet, 2014).…”

Defective recruitment of motor proteins to autophagic compartments contributes to autophagic failure in aging

“…A growing number of reports have linked malfunctioning of autophagy with aging, highlighting the role of autophagy as an anti‐aging cellular mechanism (Chang, Kumsta, Hellman, Adams & Hansen, 2017; Cuervo, 2008; Garcia‐Prat et al., 2016; Madeo, Zimmermann, Maiuri & Kroemer, 2015; Rubinsztein, Marino & Kroemer, 2011). Furthermore, genetic inhibition of this degradative process recapitulates features associated with aging and age‐related diseases (Hara et al., 1997; Komatsu et al., 2006, 2007; Menzies et al., 2017). Loss of protein/organelle quality control is a universal hallmark of aging, and malfunctioning of autophagy with age contributes to this gradual accumulation of damaged proteins and dysfunctional organelles (Kaushik & Cuervo, 2015; Kennedy et al., 2014; Lopez‐Otin, Blasco, Partridge, Serrano & Kroemer, 2013).…”

The emerging roles of protein homeostasis‐governing pathways in Alzheimer's disease

“…Meanwhile, other essential autophagy‐related proteins such as Atg7 and Atg17 likewise demonstrate significant impacts toward neural homeostasis and AD progression. In particular, conditional deletion of Atg7 results in massive neuronal death, behavioral impairments, and accumulation of intracellular Aβ (Komatsu et al., 2006; Komatsu, Wang et al., 2007; Nilsson, Loganathan, Sekiguchi, Matsuba, & Hui, 2013), while Atg17 ‐null neuronal cells suffer progressive loss and aggregation of proteotoxins as well (Liang, Wang, Peng, Gan, & Guan, 2010). Moreover, conditional deficiency of Ulk1 in the central nervous system also results in neuronal loss and degeneration, which normally serves as a key kinase triggering the formation of PI3P (Joo, Wang, Frankel, Ge, & Xu, 2016) (Table 2).…”