Gene Expression Changes in the Prefrontal Cortex, Anterior Cingulate Cortex and Nucleus Accumbens of Mood Disorders Subjects That Committed Suicide

Suicidal behaviors are frequent in mood disorders patients but only a subset of them ever complete suicide. Understanding predisposing factors for suicidal behaviors in high risk populations is of major importance for the prevention and treatment of suicidal behaviors. The objective of this project was to investigate gene expression changes associated with suicide in brains of mood disorder patients by microarrays (Affymetrix HG-U133 Plus2.0) in the dorsolateral prefrontal cortex (DLPFC: 6 Non-suicides, 15 suicides), the anterior cingulate cortex (ACC: 6NS, 9S) and the nucleus accumbens (NAcc: 8NS, 13S). ANCOVA was used to control for age, gender, pH and RNA degradation, with P≤0.01 and fold change±1.25 as criteria for significance. Pathway analysis revealed serotonergic signaling alterations in the DLPFC and glucocorticoid signaling alterations in the ACC and NAcc. The gene with the lowest p-value in the DLPFC was the 5-HT2A gene, previously associated both with suicide and mood disorders. In the ACC 6 metallothionein genes were down-regulated in suicide (MT1E, MT1F, MT1G, MT1H, MT1X, MT2A) and three were down-regulated in the NAcc (MT1F, MT1G, MT1H). Differential expression of selected genes was confirmed by qPCR, we confirmed the 5-HT2A alterations and the global down-regulation of members of the metallothionein subfamilies MT 1 and 2 in suicide completers. MTs 1 and 2 are neuro-protective following stress and glucocorticoid stimulations, suggesting that in suicide victims neuroprotective response to stress and cortisol may be diminished. Our results thus suggest that suicide-specific expression changes in mood disorders involve both glucocorticoids regulated metallothioneins and serotonergic signaling in different regions of the brain

Chaperonotherapy for Alzheimer’s Disease: Focusing on HSP60

This review will analyze growing evidence suggesting a convergence between two major areas of research: Alzheimer\u2019s disease (AD) and chaperonopathies. While AD is a widely recognized medical, public health, and social problem, the chaperonopathies have not yet been acknowledged as a related burden of similar magnitude. However, recent evidence collectively indicates that such possibility exists in that AD, or at least some forms of it, may indeed be a chaperonopathy. The importance of considering this possibility cannot be overemphasized since it provides a novel point of view to examine AD and potentially suggests new therapeutic avenues. In this review, we focus on the mitochondrial chaperone HSP60 and discuss some of its biological, molecular, and pathological facets as they pertain to AD. We further illustrate how HSP60 may be an etiologic-pathogenic factor in AD and, as such, it could become a novel, effective therapeutic target. This possibility is discussed both in the light of negative chaperonotherapy, namely the development of means to inhibit HSP60 in the event its excessive activity is a disease-promoting event in AD, as well as positive chaperonotherapy, that is boosting its activity if, on the other hand, it is demonstrated that HSP60 insufficiency is a key feature of AD with such pathological consequences as causing mitochondrial dysfunction