TrkA Signalling and Parkinson’s Dementia

Cognitive impairment and dementia are the most frequently occurring nonmotor symptoms in Parkinson’s disease (PD), yet these symptoms are mostly overlooked and are not diagnosed and treated exceptionally like the cardinal motor symptoms in clinical practice. It is only in the late twentieth century that dementia has been recognized as a major clinical manifestation in PD. The possible mechanisms that cause dementia are complex with different patterns of cognitive behavior that disrupt the patient’s quality of life. It is preeminently considered that the cholinergic denervation in the basal forebrain region mediates dementia in PD. So far, dopamine-based therapy is the key objective in the treatment of PD and the nonmotor symptoms are mostly neglected. Interestingly, the loss of Tyrosine kinase receptor-A (TrkA) signaling in basal forebrain results in neuronal atrophy, which precedes cholinergic denervation and cognitive impairment. Nerve Growth Factor (NGF) binds to TrkA receptors, inducing a cascade of events like PI-3Kinase/Akt and MAPK signaling pathways that render cholinergic degeneration and upregulate the choline acetyltransferase activity and neuronal differentiation. Hence, TrkA receptor activation by small molecules might attenuate the dementia symptoms associated with PD, and may be targeted as a novel treatment strategy along with regular clinical agents.

Effect of Water Avoidance Stress on serum and urinary NGF levels in rats: diagnostic and therapeutic implications for BPS/IC patients

Nerve growth factor (NGF) is thought to play a key role in chronic pain felt by bladder pain syndrome/interstitial cystitis (BPS/IC) patients by activating its high affinity receptor tropomyosin-related kinase subtype A (Trk A). Whether this pathway is also involved in the aggravation of pain sensation during stress events was here investigated. The levels of plasmatic NGF were increased in rats submitted to Water Avoidance Stress test (WAS), compared to controls. The administration of the alpha1A adrenoceptors blocker silodosin prevented the increase of plasmatic NGF. Urinary NGF levels were also moderately increased in animals submitted to WAS. WAS increased pain behaviour score, lowered abdominal mechanical pain threshold and increase voiding bladder reflex activity. These changes were prevented by the administration of TrkA antagonist GW441756. These findings prompt the use of plasmatic NGF as diagnosis tool for chronic visceral painful conditions and opens therapeutic opportunities for TrkA receptors antagonist/NGF sequestration.

Unveiling functional motions based on point mutations in biased signaling systems: A normal mode study on Nerve Growth Factor bound to TrkA

Many receptors elicit signal transduction by activating multiple intracellular pathways. This transduction may be triggered by a nonspecific ligand, which simultaneously activates all receptor’s signaling paths. In addition, the binding of a biased ligand preferentially elicits one path over another, in a process called biased signaling. Identifying the functional motions related to each one of these distinct pathways have direct impact in the development of new efficient and specific drugs. Here we show how to detect functional motions considering the case of the NGF/TrkA-Ig2 complex. TrkA receptors activation mediated by NGF depends on specific structural motions that trigger neuronal growth, development and survival in nervous system. R221W mutation in the ngf gene impairs the nociceptive signaling. Here we show the wide spread structural effects of this mutation in the NGF/TrkA-Ig2 complex, leading to the deletion of collective motions important to TrkA activation of nociceptive signaling. Our results suggest that subtle changes in the interaction network within neurotrophic factors due to the point mutation are sufficient to inhibit necessary conformational changes for TrkA receptors activation. The methodological approach presented in this article based conjunctively on normal mode analysis and the experimentally observed functional alterations due to point mutations provides an essential tool for unveiling the structural changes and motions related to the disease, that in turn could be important for a drug design study.

A Pro-Nerve Growth Factor (proNGF) and NGF Binding Protein, α2-Macroglobulin, Differentially Regulates p75 and TrkA Receptors and Is Relevant to NeurodegenerationEx VivoandIn Vivo

Nerve growth factor (NGF) is generated from a precursor, proNGF, that is proteolytically processed. NGF preferentially binds a trophic tyrosine kinase receptor, TrkA, while proNGF binds a neurotrophin receptor (NTR), p75NTR, that can have neurotoxic activity. Previously, we along with others showed that the soluble protein α2-macroglobulin (α2M) is neurotoxic. Toxicity is due in part to α2M binding to NGF and inhibiting trophic activity, presumably by preventing NGF binding to TrkA. However, the mechanisms remained unclear. Here, we showex vivoandin vivothree mechanisms for α2M neurotoxicity. First, unexpectedly the α2M-NGF complexes do bind TrkA receptors but do not induce TrkA dimerization or activation, resulting in deficient trophic support. Second, α2M makes stable complexes with proNGF, conveying resistance to proteolysis that results in more proNGF and less NGF. Third, α2M-proNGF complexes bind p75NTRand are more potent agonists than free proNGF, inducing tumor necrosis factor alpha (TNF-α) production. Hence, α2M regulates proNGF/p75NTRpositively and mature NGF/TrkA negatively, causing neuronal deathex vivo. These three mechanisms are operativein vivo, and α2M causes neurodegeneration in a p75NTR- and proNGF-dependent manner. α2M could be exploited as a therapeutic target, or as a modifier of neurotrophin signals.