Glaucoma is an optic neuropathy characterized by progressive degeneration of retinal ganglion cells (RGCs) and visual loss. Although one of the highest risk factors for glaucoma is elevated intraocular pressure (IOP) and reduction in IOP is the only proven treatment, the mechanism of IOP regulation is poorly understood. We report that the P2Y6 receptor is critical for lowering IOP and that ablation of the P2Y6 gene in mice (P2Y6KO) results in hypertensive glaucoma–like optic neuropathy. Topically applied uridine diphosphate, an endogenous selective agonist for the P2Y6 receptor, decreases IOP. The P2Y6 receptor was expressed in nonpigmented epithelial cells of the ciliary body and controlled aqueous humor dynamics. P2Y6KO mice exhibited sustained elevation of IOP, age-dependent damage to the optic nerve, thinning of ganglion cell plus inner plexiform layers, and a reduction of RGC numbers. These changes in P2Y6KO mice were attenuated by an IOP lowering agent. Consistent with RGC damage, visual functions were impaired in middle-aged P2Y6KO mice. We also found that expression and function of P2Y6 receptors in WT mice were significantly reduced by aging, another important risk factor for glaucoma. In summary, our data show that dysfunctional purinergic signaling causes IOP dysregulation, resulting in glaucomatous optic neuropathy.
Youichi Shinozaki, Kenji Kashiwagi, Kazuhiko Namekata, Akiko Takeda, Nobuhiko Ohno, Bernard Robaye, Takayuki Harada, Takeshi Iwata, Schuichi Koizumi
Kit receptor tyrosine kinase is highly expressed in the developing mammalian brain, yet little is known about its contribution to neural cell development and function. Here we introduced a brain-specific conditional Kit loss-of-function mutation in mice and observed severe hypoplasia of the central nervous system. This was accompanied by an increase in apoptotic cell death in the early embryonic brain and the gradual loss of the self-renewal capacity of neuronal stem/precursor cells. A single copy of the brain-specific conditional Kit loss-of-function allele resulted in the observed phenotype, including impaired in vitro differentiation of neural cells from Kit-haploinsufficient embryonic stem (ES) cells. Our findings demonstrate that Kit signaling is required for the early development of neural cells. This potentially novel Kit-haploinsufficient lethal phenotype may represent an embryonic lethal phenomenon previously unobserved because of its dominantly acting nature.
Hitomi Aoki, Akira Hara, Takahiro Kunisada
BACKGROUND. Our goal was to identify changes in the metabolome in multiple sclerosis (MS) and how vitamin D supplementation alters metabolic profiles in MS patients and healthy controls. METHODS. We applied global untargeted metabolomics to plasma from a cross-sectional cohort of age- and sex-matched MS patients and controls and a second longitudinal cohort of MS patients and healthy controls who received 5,000 IU cholecalciferol daily for 90 days. We applied partial least squares discriminant analysis, weighted correlation network analysis (WGCNA), and pathway analysis to the metabolomics data. Generalized estimating equations models were used to assess change in WGCNA-identified module scores or metabolite pathways with vitamin D supplementation. RESULTS. Utilizing multiple analytical techniques, we identified metabolic alterations in oxidative stress (γ-glutamyl amino acid, glutathione) and xenobiotic metabolism (benzoate, caffeine) in MS patients compared with healthy controls in the first cohort. In the vitamin D supplementation cohort, we identified two sets of metabolites altered differentially between MS patients and healthy controls with vitamin D supplementation. The first included markers of oxidative stress and protein oxidation (P = 0.006), while the second contained lysolipids and fatty acids (P = 0.03). CONCLUSIONS. Using metabolomics, we identified alterations in oxidative stress and xenobiotic metabolism in MS patients and subsequently demonstrated a reduction of oxidative stress markers with vitamin D supplementation in healthy controls but not in MS patients. We demonstrate the utility of metabolomics in identifying aberrant metabolic processes and in monitoring the ability of therapeutic interventions to correct these abnormalities. TRIAL REGISTRATION. ClinicalTrials.gov NCT01667796. FUNDING. This study was supported by NIH grant K23 NS067055, grants from the Race to Erase MS, the National Multiple Sclerosis Society, the American Academy of Neurology, and North American Research Committee on Multiple Sclerosis.
Pavan Bhargava, Kathryn C. Fitzgerald, Peter A. Calabresi, Ellen M. Mowry
BACKGROUND. Noninvasive detection of Alzheimer’s disease (AD) with high specificity and sensitivity can greatly facilitate identification of at-risk populations for earlier, more effective intervention. AD patients exhibit a myriad of retinal pathologies, including hallmark amyloid β-protein (Aβ) deposits. METHODS. Burden, distribution, cellular layer, and structure of retinal Aβ plaques were analyzed in flat mounts and cross sections of definite AD patients and controls (n = 37). In a proof-of-concept retinal imaging trial (n = 16), amyloid probe curcumin formulation was determined and protocol was established for retinal amyloid imaging in live patients. RESULTS. Histological examination uncovered classical and neuritic-like Aβ deposits with increased retinal Aβ42 plaques (4.7-fold; P = 0.0063) and neuronal loss (P = 0.0023) in AD patients versus matched controls. Retinal Aβ plaque mirrored brain pathology, especially in the primary visual cortex (P = 0.0097 to P = 0.0018; Pearson’s r = 0.84–0.91). Retinal deposits often associated with blood vessels and occurred in hot spot peripheral regions of the superior quadrant and innermost retinal layers. Transmission electron microscopy revealed retinal Aβ assembled into protofibrils and fibrils. Moreover, the ability to image retinal amyloid deposits with solid-lipid curcumin and a modified scanning laser ophthalmoscope was demonstrated in live patients. A fully automated calculation of the retinal amyloid index (RAI), a quantitative measure of increased curcumin fluorescence, was constructed. Analysis of RAI scores showed a 2.1-fold increase in AD patients versus controls (P = 0.0031). CONCLUSION. The geometric distribution and increased burden of retinal amyloid pathology in AD, together with the feasibility to noninvasively detect discrete retinal amyloid deposits in living patients, may lead to a practical approach for large-scale AD diagnosis and monitoring. FUNDING. National Institute on Aging award (AG044897) and The Saban and The Marciano Family Foundations.
Yosef Koronyo, David Biggs, Ernesto Barron, David S. Boyer, Joel A. Pearlman, William J. Au, Shawn J. Kile, Austin Blanco, Dieu-Trang Fuchs, Adeel Ashfaq, Sally Frautschy, Gregory M. Cole, Carol A. Miller, David R. Hinton, Steven R. Verdooner, Keith L. Black, Maya Koronyo-Hamaoui
BACKGROUND. Food intake is guided by homeostatic needs and by the reward value of food, yet the exact relation between the two remains unclear. The aim of this study was to investigate the influence of different metabolic states and hormonal satiety signaling on responses in neural reward networks. METHODS. Twenty-three healthy participants underwent functional magnetic resonance imaging while performing a task distinguishing between the anticipation and the receipt of either food- or monetary-related reward. Every participant was scanned twice in a counterbalanced fashion, both during a fasted state (after 24 hours fasting) and satiety. A functional connectivity analysis was performed to investigate the influence of satiety signaling on activation in neural reward networks. Blood samples were collected to assess hormonal satiety signaling. RESULTS. Fasting was associated with sensitization of the striatal reward system to the anticipation of food reward irrespective of reward magnitude. Furthermore, during satiety, individual ghrelin levels were associated with increased neural processing during the expectation of food-related reward. CONCLUSIONS. Our findings show that physiological hunger stimulates food consumption by specifically increasing neural processing during the expectation (i.e., incentive salience) but not the receipt of food-related reward. In addition, these findings suggest that ghrelin signaling influences hedonic-driven food intake by increasing neural reactivity during the expectation of food-related reward. These results provide insights into the neurobiological underpinnings of motivational processing and hedonic evaluation of food reward. TRIAL REGISTRATION. ClinicalTrials.gov NCT03081585. FUNDING. This work was supported by the German Competence Network on Obesity, which is funded by the German Federal Ministry of Education and Research (FKZ 01GI1122E).
Joe J. Simon, Anne Wetzel, Maria Hamze Sinno, Mandy Skunde, Martin Bendszus, Hubert Preissl, Paul Enck, Wolfgang Herzog, Hans-Christoph Friederich
Parkinson’s disease (PD) is a progressive neurodegenerative disease with devastating clinical manifestations. In PD, neuronal death is associated with intracellular aggregates of the neuronal protein α-synuclein known as Lewy bodies. Although the cause of sporadic PD is not well understood, abundant clinical and pathological evidence show that misfolded α-synuclein is found in enteric nerves before it appears in the brain. This suggests a model in which PD pathology originates in the gut and spreads to the central nervous system via cell-to-cell prion-like propagation, such that transfer of misfolded α-synuclein initiates misfolding of native α-synuclein in recipient cells. We recently discovered that enteroendocrine cells (EECs), which are part of the gut epithelium and directly face the gut lumen, also possess many neuron-like properties and connect to enteric nerves. In this report, we demonstrate that α-synuclein is expressed in the EEC line, STC-1, and native EECs of mouse and human intestine. Furthermore, α-synuclein–containing EECs directly connect to α-synuclein–containing nerves, forming a neural circuit between the gut and the nervous system in which toxins or other environmental influences in the gut lumen could affect α-synuclein folding in the EECs, thereby beginning a process by which misfolded α-synuclein could propagate from the gut epithelium to the brain.
Rashmi Chandra, Annie Hiniker, Yien-Ming Kuo, Robert L. Nussbaum, Rodger A. Liddle
Degenerative cervical myelopathy (DCM) is the most common progressive nontraumatic spinal cord injury. The most common recommended treatment is surgical decompression, although the optimal timing of intervention is an area of ongoing debate. The primary objective of this study was to assess whether a delay in decompression could influence the extent of ischemia-reperfusion injury and alter the trajectory of outcome in DCM. Using a DCM mouse model, we show that decompression acutely led to a 1.5- to 2-fold increase in levels of inflammatory cytokines within the spinal cord. Delayed decompression was associated with exacerbated reperfusion injury, astrogliosis, and poorer neurological recovery. Additionally, delayed decompression was associated with prolonged elevation of inflammatory cytokines and an exacerbated peripheral monocytic inflammatory response (P < 0.01 and 0.001). In contrast, early decompression led to resolution of reperfusion-mediated inflammation, neurological improvement, and reduced hyperalgesia. Similar findings were observed in subjects from the CSM AOSpine North America and International studies, where delayed decompressive surgery resulted in poorer neurological improvement compared with patients with an earlier intervention. Our data demonstrate that delayed surgical decompression for DCM exacerbates reperfusion injury and is associated with ongoing enhanced levels of cytokine expression, microglia activation, and astrogliosis, and paralleled with poorer neurological recovery.
Pia M. Vidal, Spyridon K. Karadimas, Antigona Ulndreaj, Alex M. Laliberte, Lindsay Tetreault, Stefania Forner, Jian Wang, Warren D. Foltz, Michael G. Fehlings
Microglia play a critical role in the development and homeostasis of the CNS. While mobilization of microglia is critical for a number of pathologies, understanding of the mechanisms of their migration in vivo is limited and often based on similarities to macrophages. Kindlin3 deficiency as well as Kindlin3 mutations of integrin-binding sites abolish both integrin inside-out and outside-in signaling in microglia, thereby resulting in severe deficiencies in cell adhesion, polarization, and migration in vitro, which are similar to the defects observed in macrophages. In contrast, while Kindlin3 mutations impaired macrophage mobilization in vivo, they had no effect either on the population of microglia in the CNS during development or on mobilization of microglia and subsequent microgliosis in a model of multiple sclerosis. At the same time, acute microglial response to laser-induced injury was impaired by the lack of Kindlin3-integrin interactions. Based on 2-photon imaging of microglia in the brain, Kindlin3 is required for elongation of microglial processes toward the injury site and formation of phagosomes in response to brain injury. Thus, while Kindlin3 deficiency in human subjects is not expected to diminish the presence of microglia within CNS, it might delay the recovery process after injury, thereby exacerbating its complications.
Julia Meller, Zhihong Chen, Tejasvi Dudiki, Rebecca M. Cull, Rakhilya Murtazina, Saswat K. Bal, Elzbieta Pluskota, Samantha Stefl, Edward F. Plow, Bruce D. Trapp, Tatiana V. Byzova
Many extremely preterm infants (born before 28 gestational weeks [GWs]) develop cognitive impairment in later life, although the underlying pathogenesis is not yet completely understood. Our examinations of the developing human neocortex confirmed that neuronal migration continues beyond 23 GWs, the gestational week at which extremely preterm infants have live births. We observed larger numbers of ectopic neurons in the white matter of the neocortex in human extremely preterm infants with brain injury and hypothesized that altered neuronal migration may be associated with cognitive impairment in later life. To confirm whether preterm brain injury affects neuronal migration, we produced brain damage in mouse embryos by occluding the maternal uterine arteries. The mice showed delayed neuronal migration, ectopic neurons in the white matter, altered neuronal alignment, and abnormal corticocortical axonal wiring. Similar to human extremely preterm infants with brain injury, the surviving mice exhibited cognitive deficits. Activation of the affected medial prefrontal cortices of the surviving mice improved working memory deficits, indicating that decreased neuronal activity caused the cognitive deficits. These findings suggest that altered neuronal migration altered by brain injury might contribute to the subsequent development of cognitive impairment in extremely preterm infants.
Ken-ichiro Kubo, Kimiko Deguchi, Taku Nagai, Yukiko Ito, Keitaro Yoshida, Toshihiro Endo, Seico Benner, Wei Shan, Ayako Kitazawa, Michihiko Aramaki, Kazuhiro Ishii, Minkyung Shin, Yuki Matsunaga, Kanehiro Hayashi, Masaki Kakeyama, Chiharu Tohyama, Kenji F. Tanaka, Kohichi Tanaka, Sachio Takashima, Masahiro Nakayama, Masayuki Itoh, Yukio Hirata, Barbara Antalffy, Dawna D. Armstrong, Kiyofumi Yamada, Ken Inoue, Kazunori Nakajima
Motor dysfunction is a prominent and disabling feature of Huntington’s disease (HD), but the molecular mechanisms that dictate its onset and progression are unknown. The N-methyl-D-aspartate receptor 2A (NR2A) subunit regulates motor skill development and synaptic plasticity in medium spiny neurons (MSNs) of the striatum, cells that are most severely impacted by HD. Here, we document reduced NR2A receptor subunits on the dendritic membranes and at the synapses of MSNs in zQ175 mice that model HD. We identify that SorCS2, a vacuolar protein sorting 10 protein–domain (VPS10P-domain) receptor, interacts with VPS35, a core component of retromer, thereby regulating surface trafficking of NR2A in MSNs. In the zQ175 striatum, SorCS2 is markedly decreased in an age- and allele-dependent manner. Notably, SorCS2 selectively interacts with mutant huntingtin (mtHTT), but not WT huntingtin (wtHTT), and is mislocalized to perinuclear clusters in striatal neurons of human HD patients and zQ175 mice. Genetic deficiency of SorCS2 accelerates the onset and exacerbates the motor coordination deficit of zQ175 mice. Together, our results identify SorCS2 as an interacting protein of mtHTT and demonstrate that impaired SorCS2-mediated NR2A subunit trafficking to dendritic surface of MSNs is, to our knowledge, a novel mechanism contributing to motor coordination deficits of HD.
Qian Ma, Jianmin Yang, Teresa A. Milner, Jean-Paul G. Vonsattel, Mary Ellen Palko, Lino Tessarollo, Barbara L. Hempstead
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