Crisford, A. | Search bioRxiv

bioRxiv2021

Age-related changes in Tau and Autophagy in human brain in the absence of neurodegeneration

Tau becomes abnormally hyper-phosphorylated and aggregated in tauopathies like Alzheimers disease (AD). As age is the greatest risk factor for developing AD, it is important to understand how tau protein itself, and the pathways implicated in its turnover, change during aging. We investigated age-related changes in total and phosphorylated tau in brain samples from two cohorts of cognitively normal individuals spanning 19-74 years, without overt neurodegeneration. One cohort utilised resected tissue and the other used post-mortem tissue. Total soluble tau levels declined with age in both cohorts. Phosphorylated tau was undetectable in the post-mortem tissue but was clearly evident in the resected tissue and did not undergo significant age-related change. To ascertain if the decline in soluble tau was correlated with age-related changes in autophagy, three markers of autophagy were tested but only two appeared to increase with age and the third was unchanged. This implies that in individuals who do not develop neurodegeneration, there is an age-related reduction in soluble tau which could potentially be due to age-related changes in autophagy. Thus, to explore how an age-related increase in autophagy might influence tau-mediated dysfunctions in vivo, autophagy was enhanced in a Drosophila model and all age-related tau phenotypes were significantly ameliorated. These data shed light on age-related physiological changes in proteins implicated in AD and highlights the need to study pathways that may be responsible for these changes. It also demonstrates the therapeutic potential of interventions that upregulate turnover of aggregate-prone proteins during aging.

neuroscience↗

bioRxiv2018

Identification and characterisation of serotonin signalling in the potato cyst nematode Globodera pallida reveals new targets for crop protection

Plant parasitic nematodes are microscopic pests that invade plant roots and cause extensive damage to crops worldwide. To investigate mechanisms underpinning their parasitic behaviour we used a chemical biology approach: We discovered that reserpine, a plant alkaloid known for its antagonism of the mammalian vesicular monoamine transporter VMAT and ability to impart a global depletion of synaptic biogenic amines in the nervous system, potently impairs the ability of the potato cyst nematode Globodera pallida to enter the host plant root. We show that this effect of reserpine is mediated by an inhibition of serotonergic signalling that is essential for activation of the stylet, a lance-like organ that protrudes from the mouth of the worm and which is used to pierce the host root to gain access. Prompted by this we identified core molecular components of G. pallida serotonin signalling encompassing the target of reserpine, VMAT; the synthetic enzyme for serotonin, tryptophan hydroxylase; the G protein coupled receptor SER-7 and the serotonin-gated chloride channel MOD-1. We found that inhibitors of tryptophan hydroxylase, SER-7 and MOD-1 phenocopy the plant protecting action of reserpine. Thus targeting the serotonin signalling pathway presents a promising new route to control plant parasitic nematodes.\n\nSummaryIndian snakeroot, an herbal medicine prepared from the roots of the shrub Rauwolfia serpentina, has been used for centuries for its calming action. The major active constituent is reserpine which works by depleting a specific class of mood regulating chemical in the brain, the biogenic amines. We have discovered a remarkable effect of reserpine on a pest of global concern, the plant parasitic nematodes. These microscopic worms invade the roots of crops presenting a severe threat to food production. We show that reserpine disables serotonin signalling in the worms brain that regulates the rhythmic thrusting of the stylet: a lance-like structure that protrudes from its mouth to pierce the plant root and which is essential to its parasitic lifecycle. Thus, reserpine joins nicotine as another intriguing example of Nature evolving its own protection against pests. We have identified key components of the serotonin signalling pathway in the potato cyst nematode Globodera pallida and show that chemicals that target these sites inhibit the ability of the nematode to invade its host plant. We conclude that biogenic amine transmitters are intimately involved in the worms parasitic behaviour and provide a new discrete route to crop protection.

pharmacology and toxicology↗