TAR DNA-binding protein 43 (TDP-43) inclusions are pathological hallmarks of patients with frontotemporal lobar degeneration (FTLD) and amyotrophic lateral sclerosis (ALS). Loss of TDP-43 in zebrafish engenders a severe muscle and vascular phenotype with a concomitant elevation of filamin C (FLNC) levels, an observation confirmed in the frontal cortex of FTLD-TDP patients. Here, we aimed to further assess the contribution of FLNC to frontotemporal dementia (FTD) etiology. We conducted a mutational screening of FLNC in a cohort of 529 unrelated Belgian FTD and FTD-ALS patients, and a control cohort of 920 unrelated and age-matched individuals. Additionally we performed an in-depth characterization of FLNC expression levels in FTD patients and a murine FTD model. In total 68 missense variants were identified of which 19 (MAF < 1 %) were patient-only. Gene burden analysis demonstrated a significant association between the presence of rare variants in FLNC and disease (P = 0.0349, RR = 1.46 [95 % CI 1.03–2.07]). Furthermore, elevated FLNC expression levels, observed previously in FTLD-TDP patients, were mainly attributable to FTD patients with the progranulin (GRN) p.0(IVS1 + 5G > C) loss-of-function mutation. Increased FLNC levels were, to a lesser extent, also identified in a FLNC p.V831I variant carrier and in FTD patients with the p.R159H mutation in valosin-containing protein (VCP). The GRN-associated increase of FLNC was confirmed in the frontal cortex of aged Grn knockout mice starting at 16–18 months of age. Combined quantitative proteomic and bioinformatic analyses of the frontal cortex of FTD patients possessing elevated FLNC levels, identified multiple altered protein factors involved in accelerated aging, neurodegeneration and synaptogenesis. Our findings further support the involvement of aberrant FLNC expression levels in FTD pathogenesis. Identification of increased FLNC levels in aged Grn mice and impaired pathways related to aging and neurodegeneration, implies a potential role for FLNC in mediating or accelerating the aging process.
Coordinated and constructive physical activity is correlated with the maintenance of cognitive function in humans. Voluntary running also enhances neuroplasticity in adult and aging rodents, but the molecular pathways underlying these effects are still being elucidated. Considering the multifactorial nature of the biochemical links between physical activity and neurophysiology it is likely that there are many pharmacological mechanisms by which the beneficial actions of exercise can be effectively reproduced using chemical agents. Most studies to date have focused on brain-derived neurotrophic factor (BDNF) as a signaling target for the enhancement of neuronal function by exercise. The goal of the current review is to move beyond BDNF by exploring the diversity of molecular pathways regulated by physical activity in a variety of situations. We will discuss the availability and mechanism of action for several diverse physical activity pharmacomimetics. As physical activity enhances both neuroplasticity and cognition, understanding the molecular targets for these effects may lead to the development of protent new therapeutic interventions for age-related neurodegenerative conditions such as Alzheimer's disease.
The aim of this study was to find an effective treatment for the genetic form of diabetes that is present in some Huntington's disease patients and in Huntington's disease mouse models. Huntington's disease is a neurodegenerative disorder caused by a polyglutamine expansion within the huntingtin protein. Huntington's disease patients exhibit neuronal dysfunction/degeneration, chorea, and progressive weight loss. Additionally, they suffer from abnormalities in energy metabolism affecting both the brain and periphery. Similarly to Huntington's disease patients, mice expressing the mutated human huntingtin protein also exhibit neurodegenerative changes, motor dysfunction, perturbed energy metabolism, and elevated blood glucose levels.Huntington's disease mice were treated with an FDA-approved antidiabetic glucagon-like peptide 1 receptor agonist, exendin-4 (Ex-4), to test whether euglycemia could be achieved, whether pancreatic dysfunction could be alleviated, and whether the mice showed any neurological benefit. Blood glucose and insulin levels and various appetite hormone concentrations were measured during the study. Additionally, motor performance and life span were quantified and mutant huntingtin (mhtt) aggregates were measured in both the pancreas and brain.Ex-4 treatment ameliorated abnormalities in peripheral glucose regulation and suppressed cellular pathology in both brain and pancreas in a mouse model of Huntington's disease. The treatment also improved motor function and extended the survival time of the Huntington's disease mice. These clinical improvements were correlated with reduced accumulation of mhtt protein aggregates in both islet and brain cells.Targeting both peripheral and neuronal deficits, Ex-4 is an attractive agent for therapeutic intervention in Huntington's disease patients suffering from diabetes.
To assess the clinical, radiologic, myopathologic, and proteomic findings in a patient manifesting a multisystem proteinopathy due to a homozygous valosin-containing protein gene (VCP) mutation previously reported to be pathogenic in the heterozygous state.We studied a 36-year-old male index patient and his father, both presenting with progressive limb-girdle weakness. Muscle involvement was assessed by MRI and muscle biopsies. We performed whole-exome sequencing and Sanger sequencing for segregation analysis of the identified p.Arg159His VCP mutation. To dissect biological disease signatures, we applied state-of-the-art quantitative proteomics on muscle tissue of the index case, his father, 3 additional patients with VCP-related myopathy, and 3 control individuals.The index patient, homozygous for the known p.Arg159His mutation in VCP, manifested a typical VCP-related myopathy phenotype, although with a markedly high creatine kinase value and a relatively early disease onset, and Paget disease of bone. The father exhibited a myopathy phenotype and discrete parkinsonism, and multiple deceased family members on the maternal side of the pedigree displayed a dementia, parkinsonism, or myopathy phenotype. Bioinformatic analysis of quantitative proteomic data revealed the degenerative nature of the disease, with evidence suggesting selective failure of muscle regeneration and stress granule dyshomeostasis.We report a patient showing a multisystem proteinopathy due to a homozygous VCP mutation. The patient manifests a severe phenotype, yet fundamental disease characteristics are preserved. Proteomic findings provide further insights into VCP-related pathomechanisms.
Mammalian gonadotropin-releasing hormone (GnRH I: pGlu-His-Trp-Ser-Tyr-Gly-Leu-Arg-Pro-Gly-NH 2 ) stimulates pituitary gonadotropin secretion, which in turn stimulates the gonads. Whereas a hypothalamic form of GnRH of variable structure (designated type I) had been shown to regulate reproduction through a cognate type I receptor, it has recently become evident that most vertebrates have one or two other forms of GnRH. One of these, designated type II GnRH (GnRH II: pGlu-His-Ser-His-Gly-Trp-Tyr-Pro-Gly-NH 2 ), is conserved from fish to man and is widely distributed in the brain, suggesting important neuromodulatory functions such as regulating K + channels and stimulating sexual arousal. We now report the cloning of a type II GnRH receptor from marmoset cDNA. The receptor has only 41% identity with the type I receptor and, unlike the type I receptor, has a carboxyl-terminal tail. The receptor is highly selective for GnRH II. As with the type I receptor, it couples to G α q/11 and also activates extracellular signal-regulated kinase (ERK1/2) but differs in activating p38 mitogen activated protein (MAP) kinase. The type II receptor is more widely distributed than the type I receptor and is expressed throughout the brain, including areas associated with sexual arousal, and in diverse non-neural and reproductive tissues, suggesting a variety of functions. Surprisingly, the type II receptor is expressed in the majority of gonadotropes. The presence of two GnRH receptors in gonadotropes, together with the differences in their signaling, suggests different roles in gonadotrope functioning.
The hyper-complex aging process is a major risk factor for progressive diseases, e.g. Alzheimer's disease, atherosclerosis and Type II diabetes. ‘Pathological’ aging and these age-related disorders demonstrate a considerable functional overlap, i.e. progressive decline of cell stress resilience, energy metabolism dysfunction and oxidative DNA damage. Complex pathologies such as aging likely involve the coordination of multiple signaling pathways. The protein factors that facilitate communication between the subnetworks are termed ‘keystone’ proteins. These proteins coordinate responses to dynamic molecular events through protein-protein interaction organization, binding to multiple partners, allowing bridging/connecting of multisystem processes. We have previously identified one such ‘aging keystone’, GIT2 (G protein-coupled receptor kinase interacting protein 2). As a scaffold protein GIT2 is not a classical drug target. To identify a potential therapeutically-targetable factor, e.g. G protein-coupled receptor (GPCR), that controls GIT2 expression/function we investigated co-expression variance in tissues from GIT2 knockout (GIT2KO) mice. Unbiased transcriptomic analysis of these tissues, demonstrated a consistent co-expression relationship of GIT2 with Relaxin family peptide receptor 3 (RXFP3). Interestingly these two proteins demonstrate considerable functional overlaps related to metabolic aging patterns, e.g. both proteins play important roles in cell stress resilience and energy metabolism. To further connect these two factors, within an aging context, we investigated whether, like GIT2, RXFP3 was associated with oxidative stress or DNA damage reponse (DDR). Hence we demonstrated that like GIT2, RXFP3 physically responded to oxidative stress, showing a translocation from the plasma membrane towards the nucleus and cytoskeleton. This reaction, in absence of the cognate peptide ligand (relaxin 3 – RLN3), indicates that this receptor, like GIT2, may be an oxidative stress sensor involved in DDR processes. Expanding this finding we analyzed the effect of oxidizing and DNA-damaging stressors on the binding partners of RXFP3 using SILAC-based affinity-purification mass spectrometry (AP-MS). Investigating the stress-induced binding partners of RXFP3 showed the presence of multiple proteins linked to DDR and cell cycle control. Extending our investigation we next found that i) RXFP3 expression is increased in response to DNA damage agents and ii) overexpression, or RLN3-mediated stimulation, of RXFP3 attenuates DNA damage, evidenced by reduced yH2AX, ATM and BRCA1 phosphorylation. The functional synergies shown by RXFP3 and GIT2, with respect to stress sensation and DDR functions encouraged us to believe that this receptor-signaling protein system may form a crucial signaling system that regulates cellular degradation after DNA damage and/or aging, and thus represents a novel strategy to attenuate the rate of age-related damage accumulation. Support or Funding Information This work was supported by the FWO-OP/Odysseus program (42/FA010100/32/6484), FWO Travelling Fellowship Program (V4.161.17N), GOA progam, BOF (33931) and Erasmus+. Visualization of the stress sensor Relaxin Family Peptide 3 receptor (RXFP3) interactome analysis after affinity-purification mass spectrometry (AP-MS). We analyzed the interacting proteins for RXFP3 after causing oxidative DNA damage in cells. Only proteins showing a selective binding (expression ratio >1.5) were analyzed using natural language processing giving a clear appreciation of our data set. Here we see that RXFP3 interacts with proteins involved in DNA damage response processes. This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
The extensive prevalence of Alzheimers disease (AD) places a tremendous burden physiologically, socially and economically upon those directly suffering and those caring for sufferers themselves. Considering the steady increases in numbers of patients diagnosed with Alzheimers, the number of effective pharmacotherapeutic strategies to tackle the disease is still relatively few. As with many other neurodegenerative mechanisms, AD, is characterized by the continued presence and accumulation of cytotoxic protein aggregates, i.e. of beta-amyloid and the microtubule associated protein, tau. Therefore, one novel therapeutic avenue for the treatment of AD may be the actual targeting of factors that control protein synthesis, packaging and degradation. One of the prime cellular targets that, if effectively modulated, could accomplish this is the endoplasmic reticulum (ER). The ER can not only control cellular protein synthesis, trafficking and degradation but it is also closely associated with cytoprotective mechanisms, including calcium ion regulation and unfolded protein responses. This review will delineate some of the most important functional physiological features of the ER that, if effectively modulated, could result in beneficial amelioration or remediation of the negative cellular aspects of AD initiation and progression. While not a classical drug target, even with minimal levels of beneficial modulation, its multifactorial efficacy may amplify small effects resulting in significant therapeutic efficacy.
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