Abstract:

The pathogenesis of these diseases involves mitochondrial dysfunction/oxidative stress, programmed cell death, abnormal protein aggregation, trafficking, and/or degradation. In most cases, the end stage neuropathology is characterized by a highly specific distribution of abnormal protein aggregates in disease specific patterns in the affected neuronal populations. Although clinical treatments for neurodegenerative disorders have progressed over the years with some promising results, the availability of treatments that can limit or halt neurodegenerative disorders continues to remain limited. A challenging approach to obtain results more close to the patient's treatment could be to dissect the role and the action mechanisms of endogenous substances well known for their neuroprotective effects. Sex steroid hormone estrogens, prevalent in women, seem to be good candidates for these studies. Indeed, a growing number of evidence concerning structural, cellular, and molecular differences in diverse male and female brain regions could explain male and female diverse response to environmental challenges and different vulnerabilities to behavioral and neurological disorders. Striking differences in symptomatology, prevalence, progression, and severity between sexes occur in several neurodegenerative diseases. Although potential sex differences concerning HD are poorly defined, few reports suggest that the age of onset of HD is higher and the course of disease is more moderate in women compared with men. In addition, animal models of HD indicate sex-related differences in the HD phenotype (www.epicentro.iss.it). As a whole, these evidences point to a substantial beneficial influence of 17β-estradiol (the most efficient within estrogens; E2) against the development and progression of neurodegenerative diseases. As a whole, these results allow us to define a novel neuroprotective axis, consisting of E2 induction of Htt and Ngb expression levels by two different and parallel mechanisms with a convergent outcome: the arrest of apoptotic cascade and the neuron survival against oxidative stress injury. The first step depends on the mediation of ERα and culminates in Htt up-regulation. Htt expression results crucial for the realization of the other step, consisting in the increase of Ngb expression through ERβ. The existence of an E2/Htt/Ngb axis supports our working hypothesis that neuroprotection in HD could be renewed by restoring neuroglobin levels with drugs that mimickingE2-induced signal pathways can alleviate symptoms or slow the progression of HD.