, 2006 and Cheung et al., 2008). In addition, BACE1 regulates Nav ion channel levels, a major factor in neuronal excitability ( Kim et al., 2007). Finally, further relating cell stress to AD, the stress-related

second messenger ceramide can promote Cdk5-mediated phosphorylation of tau, which promotes clustering of mitochondria with the ER, enhancing mitochondrial uptake of Ca ( Darios et al., 2005 and Wen et al., 2008). Taken together, these observations delineate possible disease pathways relating energy deficits and neuronal stress to enhanced BACE1 and Aβ, and on to synapse loss, network dysregulation, hyperexcitability, further neuronal stress, and the accumulation of tau-based tangles in the neurons most vulnerable to AD. With respect XAV-939 to corticostriatal involvement selleck screening library in HD, one selective vulnerability appears to involve the connectivity properties of striatial medium-sized spiny neurons, which again express Cav1.3 channels, and whose excitation is controlled by a combination of glutamatergic inputs from neocortex and dopaminergic inputs from SNc (Bamford et al., 2004 and Cepeda et al., 2007). The cortical projections exhibit early hyperexcitation in HD, apparently leading to a toxic convergence of glutamate and dopamine signals onto the medium-sized spiny neurons,

further enhancing their vulnerability to mutant Huntingtin (Surmeier et al., 2007). This scenario highlights the potential importance of non-cell-autonomous and circuit-based mechanisms to account for selective vulnerability

in NDDs (for a conceptually related study in C. elegans, see Garcia et al., 2007). Mutant Huntingtin may have similar disrupting effects on several types of neurons and nonneuronal cells, e.g., by selectively interfering with the expression of important genes such as BDNF ( Zuccato et al., 2001) and PGC1α ( Chaturvedi et al., 2009). Reduced BDNF may impair adaptive plasticity, whereas a deficit else in inducing PGC1α expression upon stress load compromises cellular adaptation to stress protection and to enhanced mitochondrial demand. Indeed, PGC1α levels are selectively reduced in striatal medium spiny neurons, and energy deficits are a prominent and early manifestation of disease in HD. The combination of these dysregulations in afferent and target neurons may aggravate excitotoxicity selectively in striatal medium-sized spiny neurons. Specific combinations of high intrinsic neuronal vulnerabilities to stress, and stress-generating connectivity properties also seem to account for the selective vulnerability of motoneurons in ALS. Thus, spinal motoneurons vulnerable to ALS are particularly prone to hyperexcitation due to their low expression of GABAA and glycine receptors (Lorenzo et al., 2006) and differ from motoneurons consistently not affected by this disease (e.g.