Figure 1.

Model of the role of endoplasmic reticulum (ER) stress in neurodegeneration.

We propose that selective neuronal vulnerability is the consequences of two strikes of the insults that eventually lead to neurodegeneration: (A) Genetic mutations (such as mutations in HFE and SOD1) or disease related environment insults may set the adaptive ER stress predispositions and can be well-tolerated in neurons. (B) Additional insults from the external environment or internal molecular differences, which alone do not cause ER stress, toxicity to neurons may increase the ER stress level and convert the adaptive response to apoptosis and cause neuron dysfunction and death. The selective vulnerability of the particular neuronal subpopulations depends on where and when the additional insults occur.