Neuroscience
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Review
Relevance of biochemical deep phenotyping for a personalised approach to Parkinson's disease.
Parkinson's disease (PD) is a multifactorial neurodegenerative disorder characterised by the progressive loss of dopaminergic neurons in the nigrostriatal tract. The identification of disease-modifying therapies is the Holy Grail of PD research, but to date no drug has been approved as such a therapy. A possible reason is the remarkable phenotypic heterogeneity of PD patients, which can generate confusion in the interpretation of results or even mask the efficacy of a therapeutic intervention. ⋯ The analyte most studied is α-synuclein, while other studies have focused on neurofilament light chain, lysosomal proteins, inflammasome-related proteins, LRRK2 and the urinary proteome. At present, stratification of PD patients, while promising, is still a nascent approach. Deep phenotyping of patients will allow clinical researchers to identify homogeneous subgroups for the investigation of tailored disease-modifying therapies, enhancing the chances of therapeutic success.
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Mitochondrial dysfunctions have been described in Down syndrome (DS) caused by either partial or full trisomy of chromosome 21 (HSA21). Mitochondria play a crucial role in various vital functions in eukaryotic cells, especially in energy production, calcium homeostasis and programmed cell death. The function of mitochondria is primarily regulated by genes encoded in the mitochondrion and nucleus. ⋯ This includes impaired mitochondrial dynamics, structural defects and dysregulated bioenergetic profiles such as OXPHOS deficiency and reduced ATP production. Various therapeutic approaches for modulating energy deficits in DS, effects and molecular mechanism of gene therapy and drugs that exert protective effects through modulation of mitochondrial function and attenuation of oxidative stress in DS cells were discussed. It is prudent that improving DS pathophysiological conditions or quality of life may be feasible by targeting something as simple as cellular mitochondrial biogenesis and function.
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Pregnancy is associated with profound acute and long-term physiological changes, but the effects of such changes on brain injury outcomes are unclear. Here, we examined the effects of previous pregnancy and maternal experience (parity) on acute neuroinflammatory responses to lateral fluid percussion injury (FPI), a well-defined experimental traumatic brain injury (TBI) paradigm. Multiparous (2-3 pregnancies and motherhood experiences) and age-matched nulliparous (no previous pregnancy or motherhood experience) female mice received either FPI or sham injury and were euthanized 3 days post-injury (DPI). ⋯ However, multiparous females had fewer CD45+ cells near the site of injury compared to nulliparous females, which was associated with preserved aquaporin-4 polarization, suggesting that parity may influence leukocyte recruitment to the site of injury and maintenance of blood brain barrier permeability following TBI. Additionally, relative cortical Il6 gene expression following TBI was dependent on parity such that TBI increased Il6 expression in nulliparous, but not multiparous, mice. Together, this work suggests that reproductive history may influence acute neuroinflammatory outcomes following TBI in females.
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Cannabinoids regulate analgesia, which has aroused much interest in identifying new pharmacological therapies in the management of refractory pain. Voltage-gated Na+ channels (Navs) play an important role in inflammatory and neuropathic pain. In particular, Nav1.9 is involved in nociception and the understanding of its pharmacology has lagged behind because it is difficult to express in heterologous systems. ⋯ In agreement with the experimental evidence, our computer simulations revealed that ACEA binds Tyr1599 of the local anaesthetics binding site of the hNav1.9, contacting residues that bind cannabinol (CBD) in the NavMs channel. ACEA adopted a conformation remarkably similar to the crystallographic conformation of anandamide on a non-homologous protein, obstructing the Na+ permeation pathway below the selectivity filter to occupy a highly conserved binding pocket at the intracellular side. These results describe a mechanism of action, possibly involved in cannabinoid analgesia.
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Prenatal exposure to high-energy diets primes brain alterations that increase the risk of developing behavioral and cognitive failures. Alterations in the structure and connectivity of brain involved in learning and memory performance are found in adult obese murine models and in humans. However, the role of prenatal exposure to high-energy diets in the modulation of the brain's structure and function during cognitive decline remains unknown. ⋯ By using deformation-based morphometry and diffusion tensor imaging analysis we found that male offspring exposed to CAF diet showed increased volume in primary somatosensory cortex and a reduced volume of fimbria-fornix, which correlate with alterations in its white matter integrity. Biological modeling revealed that prenatal exposure to CAF diet predicts low volume in the fimbria-fornix, which was associated with anxiety in the offspring. The findings suggest that prenatal exposure to high-energy diets prime brain structural alterations related to anxiety in the offspring.