Researching the origins of depressive symptoms of Huntington's disease

About 40% of patients with Huntington's disease – a neurodegenerative pathology – have symptoms of depression, even at an early stage before the onset of typical motor symptoms of the disease. An altered function of the kinase Cdk5 – an essential enzyme in several cell signaling pathways – could explain the pathophysiology of depressive Huntington's disease behavior, according to a preclinical study in which experts from the University of Barcelona, ​​Sílvia Ginés , Verónica Brito, Albert Giralt and Jordi Alberch, of the Faculty of Medicine and Health Sciences and the Institute of Neuroscience of UB (UBNeuro), participated in the conference.

The new study, published in the journal Biological Psychiatry, highlights the design of future pharmacological strategies – based on the modeling of specific molecular pathways – to treat depression in people with Huntington's disease.

Cdk5 Kinase: essential protein in synaptic plasticity and memory

The study, led by speaker Silvia Ginés, focuses on the function of the kinase Cdk5, an enzyme essential for neuronal function. In particular, this kinase plays an important role in the expression, distribution and localization of the NMDA receptor family, essential in the physiology of the nervous system, as well as in the modeling of synaptic plasticity and the processes of 39, learning and memory.

With regard to Huntington's disease, the Cdk5 kinase has a complex involvement in the appearance of cognitive dysfunction – according to previous studies of the research team – because it is capable of altering the expression and the functionality of these receivers.

The role of Cdk5 in cognition is already known, but its potential involvement in depression is poorly understood. "Therefore, we examined whether modifications of the Cdk5 kinase could be the main cause of depressive phenotypes in Huntington," says Ginés, a member of the research group in physiopathology and treatment of neurodegenerative disorders (UB-IDIBAPS).

New molecular pathways to fight depression in people with Huntington

The results of this study showed that in murine models of the disease, Cdk5 shows higher activity in two brain regions – the nucleus accumbens and the prefrontal cortex – badociated with the processes of anxiety and depression. "However, the next step to be determined was to determine the potential impact of this modification of Cdk5 on these depressive-type processes," notes Sílvia Ginés, also a member of IDIBAPS and the Network for biomedical research on neurodegenerative diseases (CIBERNED).

In this context, the experts wanted to evaluate whether a reduction in the function of Cdk5 kinase could have therapeutic benefits in the treatment of depression in Huntington. In murine models, the phenotype of depression is previously shown by the appearance of typical cognitive and motor symptoms, that is, before neuronal degeneration.

The findings of the new study reveal that the hyperfunction of the Cdk5 kinase modifies the signaling pathway of DARPP-32 / β-adducin specifically in the cerebral region of the nucleus accumbens. This pathway has a distinguished function in dopaminergic signaling and cytoskeletal stability of the dendritic spine, so that it can induce the loss of these compounds.

According to the authors, the molecular pathways badociated with depressive type behavior in Huntington's disease may be different from typical major depression. This would explain why conventional anti-depression treatments (serotonin or monoamine collectors) have little effect or may even worsen motor symptoms in people with Huntington.

Would Cdk5 inhibitors prevent the onset of depressive phenotypes? Since Cdk5 kinase participates in several cellular processes, it would not be useful to use it as a direct therapeutic target. "It would be necessary to avoid adverse effects in other physiological pathways where this enzyme is active, which would require defining the molecules on which the Cdk5 kinase acts – in a non-functional way, to create the phenotype of depressive type, "comments the speaker Sílvia Ginés.

Depressive type symptoms and cognitive disorders: new research perspectives

The origins of depressive phenotypes in Huntington's disease models were hitherto linked to alterations in the molecular mechanisms that affected dopaminergic and serotoninergic systems, the process of neurogenesis in the hippocampus, and neurotrophic factor derived from the brain. . The new study, now published in the journal Biological Psychiatry focuses on the ability of the Cdk5 kinase to modify the DARPP-32 protein and treats this research from a preventive point of view, that is to say from the previous stages to the onset of cognitive degeneration.

"One of the current goals – notes Sílvia Ginés – is to determine if this strategy is also valid once the symptoms have appeared, then to see how long the beneficial effects last." We want to badyze whether the prevention of Onset of depressive symptoms has an effect on the onset of cognitive impairment, either because these are lighter, slower or do not appear at all ".

Another challenge for the research team is to determine whether the alteration of the Cdk5 kinase affects one of the neuronal subpopulations – with opposite effects in depression – incorporating the nucleus accumbens, the main brain region affected by the impaired function of Cdk5.

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