Current biology : CB
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Current biology : CB · Jun 2011
The kynurenine pathway modulates neurodegeneration in a Drosophila model of Huntington's disease.
Neuroactive metabolites of the kynurenine pathway (KP) of tryptophan degradation have been implicated in the pathophysiology of neurodegenerative disorders, including Huntington's disease (HD) [1]. A central hallmark of HD is neurodegeneration caused by a polyglutamine expansion in the huntingtin (htt) protein [2]. Here we exploit a transgenic Drosophila melanogaster model of HD to interrogate the therapeutic potential of KP manipulation. ⋯ We also find that genetic inhibition of tryptophan 2,3-dioxygenase (TDO), the first and rate-limiting step in the pathway, leads to a similar neuroprotective shift toward KYNA synthesis. Importantly, we demonstrate that the feeding of KYNA and 3-HK to HD model flies directly modulates neurodegeneration, underscoring the causative nature of these metabolites. This study provides the first genetic evidence that inhibition of KMO and TDO activity protects against neurodegenerative disease in an animal model, indicating that strategies targeted at two key points within the KP may have therapeutic relevance in HD, and possibly other neurodegenerative disorders.
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GABA modification plays an important role in motor cortical plasticity. We therefore hypothesized that interindividual variation in the responsiveness of the GABA system to modification influences learning capacity in healthy adults. ⋯ The magnitude of M1 GABA decrease induced by anodal tDCS correlated positively with both the degree of motor learning and the degree of fMRI signal change within the left M1 during learning. This study therefore suggests that the responsiveness of the GABAergic system to modification may be relevant to short-term motor learning behavior and learning-related brain activity.
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Mechanosensory transduction underlies touch, hearing and proprioception and requires mechanosensitive channels that are directly gated by forces; however, the molecular identities of these channels remain largely elusive. A new study has identified Piezo1 and Piezo2 as a novel class of mechanosensitive channels.
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Acute peripheral pain is reduced by multisensory interactions at the spinal level [1]. Central pain is reduced by reorganization of cortical body representations [2, 3]. We show here that acute pain can also be reduced by multisensory integration through self-touch, which provides proprioceptive, thermal, and tactile input forming a coherent body representation [4, 5]. ⋯ We show that this paradoxical release from paradoxical heat cannot be explained by low-level touch-temperature interactions alone. To reduce pain, we often clutch a painful hand with the other hand. We show here that self-touch not only gates pain signals reaching the brain [7-9] but also, via multisensory integration, increases coherence of cognitive body representations to which pain afferents project [10].