, 2008, Morimoto, 2008 and Matus et al., 2011) and consistently involve pathways that regulate energy metabolism and cell repair, which

have been implicated in the control of life span and aging (Hsu et al., 2003, Cui et al., 2006, Cohen and Dillin, 2008, Gan and Mucke, 2008 and Cohen et al., 2009). Accordingly, selective neuronal vulnerability may involve neuron specific combinations of dysfunctions in cellular stress and proteostasis pathways, aggravated by advancing age. This review focuses on the roles of specific neuronal vulnerabilities in the etiology of NDDs, i.e., on how intrinsic and environment-induced cellular stress and homeostasis pathways may intersect with the accumulation of misfolding proteins in particular vulnerable neurons to ABT-888 cell line promote disease. More detailed treatments of each NDD, and of the key roles of local microenvironment factors such as glial dysfunction, immune system engagement, and vascular dysfunction in disease

can be found in recent reviews (e.g., Zlokovic, 2005, Boillée et al., 2006b, Maragakis and Rothstein, 2006, Ballatore et al., 2007, Cepeda et al., 2007, Hawkes et al., 2007, Balch et al., 2008, Zacchigna et al., 2008, Golde and Miller, 2009, Ron-Harel and Schwartz, 2009 and Glass Ibrutinib concentration et al., 2010). As will be discussed below, a survey of disease mechanisms in

AD, PD, HD, and ALS suggests that the neurons selectively vulnerable to NDDs are particularly sensitive to particular stressors, and subject to high physiological levels of excitation and intracellular Ca loads (e.g., Lin and Beal, 2006, Palop et al., 2006, Gleichmann and Mattson, 2010 and Prahlad Cytidine deaminase and Morimoto, 2009). Further sources of intrinsic stressor load relevant to disease include genetic background, preexisting conditions (e.g., diabetes), and advancing age. In addition to such predisposing factors, disease-relevant environmental stressors can include chronic consequences of physical and ischemic lesions (Vermeer et al., 2003, Blasko et al., 2004 and Szczygielski et al., 2005), lesions left behind by previous infections, and chronic consequences of stress and environmental toxins. For example, repeated head trauma in football players is highly correlated with subsequent tauopathy with dementia (McKee et al., 2009). Based on these considerations, we discuss a stressor-load model to account for how specific neuronal subpopulations contribute to the etiology of NDDs and how familial and sporadic forms of the diseases produce comparable disease manifestations and pathology.