Thus, mice deficient in the autophagy protein Atg5 exhibited

cytoplasmic inclusions and signs of neurodegeneration ( Hara et al., 2006), absence of Atg7 in mice caused massive neurodegeneration and premature death ( Komatsu et al., 2006), and deletion of the BH3-only protein Puma, an ER stress protein, had protective effects on motoneurons in a mouse model of ALS ( Kieran et al., 2007). These findings have led to the notion that NDDs may involve cell-specific interplays between protein misfolding and cellular stress pathways ( Figure 1). Because the effectiveness of the cell homeostasis pathways is known to diminish with advancing age, their involvement in NDDs ties in well with the age dependence of the neurodegenerative processes. In further support

of a close mechanistic relationship between cell homeostasis buy XAV-939 and protein Obeticholic Acid mw misfolding pathways in NDDs, the signaling pathways that relate life span and aging to organelle and energy homeostasis powerfully influence the accumulation of misfolded proteins and the effectiveness of cell stress pathways (Gan and Mucke, 2008, Prahlad and Morimoto, 2009 and Cohen et al., 2009). Groundbreaking studies in C. elegans have established that the effector of the Insulin/IGF1 pathway Daf16, which regulates longevity, also regulates the expression of HSF1 (heat shock factor 1) chaperons that control protein homeostasis in response to misfolding-induced stress ( Morley et al., 2002 and Hsu et al., 2003). Furthermore,

starvation and inhibition of the Insulin/IGF1 pathway promote autophagy pathways thought to directly promote longevity ( Hsu et al., 2003). Perhaps most interestingly in the context of NDDs, inhibiting IGF1 signaling diminishes age-related proteotoxicity MTMR9 in mice ( Cohen et al., 2009), and activation of the Insulin/IGF1 pathway promotes the accumulation of human Aβ aggregates in C. elegans, thus linking universal aging-related pathways with the accumulation of misfolded proteins implicated in AD in humans ( Hsu et al., 2003 and Prahlad and Morimoto, 2009). Along similar lines, an age-related decline in the PGC1α (peroxisome proliferator-activated receptor gamma coactivator 1-α) pathway that promotes cell plasticity, mitochondrial biogenesis, and energy production is causally related to increasing ER stress, increasing accumulation of misfolding proteins, and accelerated disease progression in animal models of NDDs ( St-Pierre et al., 2006, Weydt et al., 2006 and Cui et al., 2006). Taken together, these findings delineate a rich set of interconnected signaling pathways potentially linking advancing age, impaired protein homeostasis, ER stress, and mitochondrial dysfunction to the accumulation of particular misfolded proteins and neurodegeneration.