Inosine monophosphate dehydrogenase intranuclear inclusions are markers of aging and neuronal stress in the human substantia nigra.

We explored mechanisms involved in the age-dependent degeneration of human substantia nigra (SN) dopamine (DA) neurons. Owing to its important metabolic functions in post-mitotic neurons, we investigated the developmental and age-associated changes in the purine biosynthetic enzyme inosine monophosphate dehydrogenase (IMPDH). Tissue microarrays prepared from post-mortem samples of SN from 85 neurologically intact participants humans spanning the age spectrum were immunostained for IMPDH combined with other proteins. SN DA neurons contained two types of IMPDH structures: cytoplasmic IMPDH filaments and intranuclear IMPDH inclusions. The former were not age-restricted and may represent functional units involved in sustaining purine nucleotide supply in these highly metabolically active cells. The latter showed age-associated changes, including crystallization, features reminiscent of pathological inclusion bodies, and spatial associations with Marinesco bodies; structures previously associated with SN neuron dysfunction and death. We postulate dichotomous roles for these two subcellularly distinct IMPDH structures and propose a nucleus-based model for a novel mechanism of SN senescence that is independent of previously known neurodegeneration-associated proteins.

Emotional Response to Humour Perception and Gelotophobia Among Healthy Individuals and Patients with Schizophrenia and Depression, with Signs of a High Clinical Risk of Psychosis.

Introduction: Investigating early changes in the emotional sphere within the schizophrenia course is a perspective direction in clinical psychology and psychiatry. Intactness of positive emotions, in particular, humour perception, may be a very important resource for patients. At the same time, humour perception is very sensitive to pathological conditions, such as the fear of being laughed at, known as gelotophobia. Those with gelotophobia perceive laughter as dangerous, rather than pleasant, and they can hardly distinguish between teasing and ridicule. Gelotophobia was confirmed to be expressed among people with mental disorders. Nonetheless, knowledge relating to the fear of being laughed at, was mostly generated among the non-clinical samples. Objectives: Thus, the aim of the study was to provide more clinical data on gelotophobia manifestations associated with schizophrenia spectrum disorders; the emotional response and facial expression of patients with gelotophobia were studied, in particular, regarding their perception of humour, including during the early stages of disorders, by comparison with healthy individuals. Methods: n=30 controls and n=32 patients with schizophrenia and with depression with signs of a high clinical risk of psychosis took part. Two short videos, comic and neutral, were shown to the participants, while videotaping their facial expression, followed each by a self-reported measure of emotional responses. Participants also completed the State-Trait Anxiety Inventory, the PhoPhiKat30 and the Toronto Alexithymia Scale. Results: Gelotophobia was significantly higher within the clinical group. It correlated with a lower frequency of grins among the patients during the comic video, while this was not the case in the control group. Gelotophobia was related to state and trait anxiety in both groups, but only in the clinical group did state anxiety increase after watching the comic video. Gelotophobia correlated with alexithymia and was twice higher among the patients compared to the controls. Conclusion: Thus, gelotophobia has not only quantitative, but also qualitative specifics in patients with schizophrenia, and those with depression with signs of a clinically high risk of psychosis, compared to healthy controls.