Editorial: Neuronal Self-Defense: Compensatory Mechanisms in Neurodegenerative Disorders

Neurodegenerative diseases (ND) are characterized by the progressive loss of specific neuronal populations with consequent deterioration of brain's function. While some ND have monogenic causes, the vast majority is sporadic. Accordingly, etiology varies greatly between these conditions; the pathogenesis, however, shares important common traits. Trophic deprivation, oxidative stress, accumulation of abnormal protein aggregates, and bioenergetics defects have been in fact described in most, if not all, ND. To counterbalance these noxious stimuli cells deploy intrinsic neuroprotective responses, at least during early pathogenesis. Adaptation includes strategies to optimize energetic resources, for instance reduction of rRNA synthesis to repress translation, suppression of transcription, and bioenergetics and metabolic redesign. Additional mechanisms include potentiation of antioxidant capacity, induction of endoplasmic reticulum (ER) stress, and activation of protein quality control systems and autophagy. Strategies to potentiate these naturally occurring processes might provide foundation to devise new experimental treatments. This e-book contains a collection of reviews and original articles summarizing the state-of-the-art knowledge on protective responses sustaining neuronal survival and activity. The ultimate goal of this work is to inspire novel studies elucidating strategies to contrast these incurable disorders. The first article reviews transcriptional deregulation in Huntington's disease (HD). Francelle and colleagues point out that while transcriptional changes are directly caused by mutant huntingtin, they may also represent a response to secondary stress conditions triggered by dysfunctional transcriptional machineries. They speculate that transient expression changes typical of HD may represent a self-defense mechanism because some of these altered genes activate pro-survival functions, which may be impaired during aging. Hence, the investigation of gene expression changes with aging in the striatum, the brain region mostly affected in HD, might help to develop strategies to modify mutant huntingtin toxicity (Francelle et al.). In line with this concept, Stilling and colleagues show how aging is associated with changes in gene expression and in RNA splicing, and with the upregulation of immune system functions in the hippocampus (Stilling et al.). Interestingly, affected genes are involved in synaptic function, therefore suggesting a potential pathogenic link between age-dependent transcriptional alterations and late onset of Alzheimer's disease (AD) (Stilling et al.). A second original research article illustrates how two transcription factors important for the development of dopaminergic neurons also play a role in their maintenance in adulthood. Previous studies indicated that haploinsufficiency of the transcription factor Foxa 2 leads to abnormalities in motor behavior in old age and an associated progressive loss of …