The development of new therapies is an arduous, time-consuming and costly task. Furthermore, the development of many compounds runs into issues related to safety. Drug repurposing, where drugs with ...established safety in humans are tested and developed for efficacy in a disease other than the one for which they were developed, is gaining traction because of its potential to overcome an initial bottleneck in the drug development process. In Bedside to Bench, Stephen Strittmatter discusses the types of scenario in which drug repurposing may be of benefit, such as when a drug is repurposed for a new molecular target or for the same target in a different disease. In Bench to Bedside, Michael Pollak focuses on a recent study that suggest that biguanides that are normally used in the treatment of diabetes could have direct cyotoxic action on cancer cells with mutations in respiratory complex I. The pharmacokinetic hurdles that may need to be overcome for this to be translated to the clinic are also discussed.
Highlights • Nogo-A limits neural repair and recovery after adult CNS injuries. • NgR1 and S1PR2 are receptors for different domains of Nogo-A. • Nogo-A and NgR1 limit experience-dependent neural ...plasticity. • Nogo-A and NgR1 stabilize synaptic, dendritic and axonal anatomy in the adult CNS.
Experience rearranges anatomical connectivity in the brain, but such plasticity is suppressed in adulthood. We examined the turnover of dendritic spines and axonal varicosities in the somatosensory ...cortex of mice lacking Nogo Receptor 1 (NgR1). Through adolescence, the anatomy and plasticity of ngr1 null mice are indistinguishable from control, but suppression of turnover after age 26 days fails to occur in ngr1−/− mice. Adolescent anatomical plasticity can be restored to 1-year-old mice by conditional deletion of ngr1. Suppression of anatomical dynamics by NgR1 is cell autonomous and is phenocopied by deletion of Nogo-A ligand. Whisker removal deprives the somatosensory cortex of experience-dependent input and reduces dendritic spine turnover in adult ngr1−/− mice to control levels, while an acutely enriched environment increases dendritic spine dynamics in control mice to the level of ngr1−/− mice in a standard environment. Thus, NgR1 determines the low set point for synaptic turnover in adult cerebral cortex.
► Turnover of synaptic anatomy is accelerated in the brain of mice lacking NgR1 ► Deletion of NgR1 in adult mice restores juvenile levels of anatomical plasticity ► NgR1 functions cell-autonomously to limit anatomical plasticity in vivo ► NgR1 expression limits the anatomical response to somatosensory input
Experience rearranges connectivity, but anatomical plasticity is restricted in adults. Akbik et al. demonstrate that Nogo Receptor 1 is required continuously and cell-autonomously to limit adult dendritic spine turnover. NgR1 determines the low set point for synaptic turnover in adult cerebral cortex.
Soluble amyloid-β oligomers (Aβo) trigger Alzheimer’s disease (AD) pathophysiology and bind with high affinity to cellular prion protein (PrPC). At the postsynaptic density (PSD), extracellular Aβo ...bound to lipid-anchored PrPC activates intracellular Fyn kinase to disrupt synapses. Here, we screened transmembrane PSD proteins heterologously for the ability to couple Aβo-PrPC with Fyn. Only coexpression of the metabotropic glutamate receptor, mGluR5, allowed PrPC-bound Aβo to activate Fyn. PrPC and mGluR5 interact physically, and cytoplasmic Fyn forms a complex with mGluR5. Aβo-PrPC generates mGluR5-mediated increases of intracellular calcium in Xenopus oocytes and in neurons, and the latter is also driven by human AD brain extracts. In addition, signaling by Aβo-PrPC-mGluR5 complexes mediates eEF2 phosphorylation and dendritic spine loss. For mice expressing familial AD transgenes, mGluR5 antagonism reverses deficits in learning, memory, and synapse density. Thus, Aβo-PrPC complexes at the neuronal surface activate mGluR5 to disrupt neuronal function.
•Among transmembrane PSD proteins, only mGluR5 couples Aβo-PrPC to Fyn kinase•mGluR5 also links Aβo-PrPC to calcium signaling and protein translation control•AD brain extract-induced dysregulation of neuronal calcium requires PrPC-mGluR5•Transgenic mouse memory deficits and synapse loss are reversed by mGluR5 antagonist
Amyloid-β oligomers trigger Alzheimer’s pathophysiology by binding to PrPC and disrupting synapses. Um et al. show that the mGluR5 metabotropic glutamate receptor links Aβo-PrPC to intracellular signaling. For AD mice, mGluR5 antagonism reverses deficits in learning, memory, and synapse density.
Progranulin (GRN) and TMEM106B are associated with several common neurodegenerative disorders including frontotemporal lobar degeneration (FTLD). A TMEM106B variant modifies GRN-associated FTLD risk. ...However, their functional relationship in vivo and the mechanisms underlying the risk modification remain unclear. Here, using transcriptomic and proteomic analyses with Grn−/− and Tmem106b−/− mice, we show that, while multiple lysosomal enzymes are increased in Grn−/− brain at both transcriptional and protein levels, TMEM106B deficiency causes reduction in several lysosomal enzymes. Remarkably, Tmem106b deletion from Grn−/− mice normalizes lysosomal protein levels and rescues FTLD-related behavioral abnormalities and retinal degeneration without improving lipofuscin, C1q, and microglial accumulation. Mechanistically, TMEM106B binds vacuolar-ATPase accessory protein 1 (AP1). TMEM106B deficiency reduces vacuolar-ATPase AP1 and V0 subunits, impairing lysosomal acidification and normalizing lysosomal protein levels in Grn−/− neurons. Thus, Grn and Tmem106b genes have opposite effects on lysosomal enzyme levels, and their interaction determines the extent of neurodegeneration.
•Transcriptomic and proteomic evidence of lysosomal dysregulation in Grn−/− mice•Tmem106b−/− mice show opposite protein changes in lysosomes•TMEM106B interacts with V-ATPase and regulates lysosomal acidification•TMEM106B deficiency rescues lysosomal, behavioral, and degenerative Grn−/− phenotypes
Klein et al. study the role of frontotemporal dementia-associated proteins in mouse models. Loss of Progranulin increases lysosomal enzymes, while TMEM106B loss impairs lysosomal acidification and reduces levels. The double mutant rescues neurodegeneration observed with single Progranulin gene loss.
...the three studies found fibrils derived from individuals who have a common, disease-protective variant of TMEM106B, as well as fibrils without that variant, indicating that the variant itself is ...not directly responsible for the propensity of TMEM106B to form fibrils. ...the cryo-electron-microscopy structures reveal evidence of a small molecule bound to TMEM106B, the identity of which remains unknown. ...TDP-43 fibrils were not observed in these studies.
Abstract Ischemic stroke is a leading cause of disability and death worldwide. Current drug treatment for stroke remains inadequate due to the existence of the blood–brain barrier. We proposed an ...innovative nanotechnology-based autocatalytic targeting approach, in which the blood–brain barrier modulator lexiscan is encapsulated in nanoparticles to enhance blood–brain barrier permeability and autocatalytically augment the brain stroke-targeting delivery efficiency of chlorotoxin-anchored nanoparticles. The nanoparticles efficiently and specifically accumulated in the brain ischemic microenvironment and the targeting efficiency autocatalytically increased with subsequent administrations. When Nogo-66 receptor antagonist peptide NEP1-40, a potential therapeutic agent for ischemic stroke, was loaded, nanoparticles significantly reduced infarct volumes and enhanced survival. Our findings suggest that the autocatalytic targeting approach is a promising strategy for drug delivery to the ischemic microenvironment inside the brain. Nanoparticles developed in this study may serve as a new approach for the clinical management of stroke.
Soluble oligomers of amyloid-beta (Aβo) are implicated by biochemical and genetic evidence as a trigger for Alzheimer's disease (AD) pathophysiology. A key step is Aβo interaction with the neuronal ...surface to initiate a cascade of altered signal transduction leading to synaptic dysfunction and damage. This review discusses neuronal cell surface molecules with high affinity selectively for oligomeric disease-associated states of Aβ, with a particular focus on the role of cellular prion protein (PrPC) in this process. Additional receptors may contribute to mediation of Aβo action, but PrPC appears to play a primary role in a number of systems. The specificity of binding, the genetic necessity in mouse models of disease and downstream signaling pathways are considered. Signal transduction downstream of Aβo complexes with PrPC involves metabotropic glutamate receptor 5 (mGluR5), Fyn kinase and Pyk2 kinase, with deleterious effects on synaptic transmission and maintenance. Current data support the hypothesis that a substantial portion of Aβo toxicity in AD is mediated after initial interaction with PrPC on the neuronal surface. As such, the interaction of Aβo with PrPC is a potential therapeutic intervention site for AD.
•Aβ oligomers trigger synaptic dysfunction in Alzheimer via neuronal receptors.•PrPC is a high affinity binding site for Aβo mediating deleterious effects in mice.•Signal transduction downstream of Aβo/PrPC involves mGluR5, Fyn and Pyk2.
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