Selective Neuronal Vulnerability in Neurodegenerative Diseases: from Stressor Thresholds to Degeneration  Smita Saxena, Pico Caroni  Neuron  Volume 71, Issue 1, Pages 35-48 (July 2011) DOI: 10.1016/j.neuron.2011.06.031 Copyright © 2011 Elsevier Inc. Terms and Conditions

Figure 1 Schematic of How Gradually Increasing Stress in Affected and Selectively Vulnerable Neurons May Underlie the Etiology and Progression of NDDs Specific NDDs may be defined by successive restrictions in the range of neurons affected by individual predispositions, local environmental factors, stress susceptibility, and sensitivity to misfolding-prone proteins. The connectivity and excitability properties of neuronal subpopulations may have a major role in determining their intrinsic sensitivity to stress. Intrinsic distinctions in the susceptibility of neurons to individual misfolding-prone proteins may account for similar disease patterns and pathology in sporadic and familial cases of the NDDs. Cascades of mutually reinforcing stress and proteostasis imbalance responses may escalate in an age-sensitive manner in affected, stress-sensitive, and misfolding-protein-sensitive neurons, causing their dysfunction and death. The accumulation of the toxic protein species may subsequently spread to other less vulnerable cells and increase their stressor load as well. Environmental factors may affect several brain systems through systemic involvement, e.g., involving the vasculature, inflammatory responses and the immune system, as well as spreading of toxic protein species. Neuron 2011 71, 35-48DOI: (10.1016/j.neuron.2011.06.031) Copyright © 2011 Elsevier Inc. Terms and Conditions