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EFhd2 is a conserved calcium binding protein linked to different neurological disorders and types of cancer. Although, EFhd2 is more abundant in neurons, it is also found in other cell types. The physiological function of this novel protein is still unclear, but it has been shown in vitro to play a role in calcium signaling, apoptosis, actin cytoskeleton, and regulation of synapse formation. Recently, EFhd2 was shown to promote cell motility by modulating the activity of Rac1, Cdc42, and RhoA. Although, EFhd2's role in promoting cell invasion and metastasis is of great interest in cancer biology, this review focusses on the evidence that links EFhd2 to Alzheimer's disease (AD) and other neurological disorders. Altered expression of EFhd2 has been documented in AD, Parkinson's disease, Huntington's disease, Amyotrophic Lateral Sclerosis, and schizophrenia, indicating that Efhd2 gene expression is regulated in response to neuropathological processes. However, the specific role that EFhd2 plays in the pathophysiology of neurological disorders is still poorly understood. Recent studies demonstrated that EFhd2 has structural characteristics similar to amyloid proteins found in neurological disorders. Moreover, EFhd2 co-aggregates and interacts with known neuropathological proteins, such as tau, C9orf72, and Lrrk2. These results suggest that EFhd2 may play an important role in the pathophysiology of neurodegenerative diseases. Therefore, the understanding of EFhd2's role in health and disease could lead to decipher molecular mechanisms that become activated in response to neuronal stress and degeneration.

The gut microbiome can impact brain health and is altered in Parkinson’s disease (PD). The vermiform appendix is a lymphoid tissue in the cecum implicated in the storage and regulation of the gut microbiota. We sought to determine whether the appendix microbiome is altered in PD and to analyze the biological consequences of the microbial alterations. We investigated the changes in the functional microbiota in the appendix of PD patients relative to controls (n = 12 PD, 16 C) by metatranscriptomic analysis. We found microbial dysbiosis affecting lipid metabolism, including an upregulation of bacteria responsible for secondary bile acid synthesis. We then quantitatively measure changes in bile acid abundance in PD relative to the controls in the appendix (n = 15 PD, 12 C) and ileum (n = 20 PD, 20 C). Bile acid analysis in the PD appendix reveals an increase in hydrophobic and secondary bile acids, deoxycholic acid (DCA) and lithocholic acid (LCA). Further proteomic and transcriptomic analysis in the appendix and ileum corroborated these findings, highlighting changes in the PD gut that are consistent with a disruption in bile acid control, including alterations in mediators of cholesterol homeostasis and lipid metabolism. Microbially derived toxic bile acids are heightened in PD, which suggests biliary abnormalities may play a role in PD pathogenesis.

Tauopathies are characterized by the abnormal buildup of tau protein, with early oligomeric forms associated with neurodegeneration and the later neurofibrillary tangles possibly conferring neuroprotection. The molecular mechanisms governing the formation of these tau species are unclear. Lately, there has been an increased focus on examining the interactions between tau and other proteins, along with their influence on the aggregation of tau. Our previous work revealed EFhd2’s association with pathological tau in animal models and tauopathy brains. Herein, we examined the impact of EFhd2 on monomeric and filamentous tau in vitro . The results demonstrated that EFhd2 incubation with monomeric full length human tau (hTau40) formed amorphous aggregates, where both EFhd2 and hTau40 colocalized. Moreover, EFhd2 is entangled with arachidonic acid (ARA)-induced filamentous hTau40. Furthermore, EFhd2-induced aggregation with monomeric and filamentous hTau40 is EFhd2 concentration dependent. Using sandwich ELISA assays, we assessed the reactivity of TOC1 and Alz50—two conformation-specific tau antibodies—to EFhd2-hTau40 aggregates (in absence and presence of ARA). No TOC1 signal was detected in EFhd2 aggregates with monomeric hTau40 whereas EFhd2 aggregates with hTau in the presence of ARA showed a higher signal compared to hTau40 filaments. In contrast, EFhd2 aggregates with both monomeric and filamentous hTau40 reduced Alz50 reactivity. Taken together, our results illustrate for the first time that EFhd2, a tau-associated protein, interacts with monomeric and filamentous hTau40 to form large aggregates that are starkly different from tau oligomers and filaments. Given these findings and previous research, we hypothesize that EFhd2 may play a role in the formation of tau aggregates. Nevertheless, further in vivo studies are imperative to test this hypothesis.

Background Hemispheric asymmetry in neuronal processes is a fundamental feature of the human brain and drives symptom lateralization in Parkinson’s disease (PD), but its molecular determinants are unknown. Here, we identify divergent epigenetic patterns involved in hemispheric asymmetry by profiling DNA methylation in isolated prefrontal cortex neurons from control and PD brain hemispheres. DNA methylation is fine-mapped at enhancers and promoters, genome-wide, by targeted bisulfite sequencing in two independent sample cohorts. Results We find that neurons of the human prefrontal cortex exhibit hemispheric differences in DNA methylation. Hemispheric asymmetry in neuronal DNA methylation patterns is largely mediated by differential CpH methylation, and chromatin conformation analysis finds that it targets thousands of genes. With aging, there is a loss of hemispheric asymmetry in neuronal epigenomes, such that hemispheres epigenetically converge in late life. In neurons of PD patients, hemispheric asymmetry in DNA methylation is greater than in controls and involves many PD risk genes. Epigenetic, transcriptomic, and proteomic differences between PD hemispheres correspond to the lateralization of PD symptoms, with abnormalities being most prevalent in the hemisphere matched to side of symptom predominance. Hemispheric asymmetry and symptom lateralization in PD is linked to genes affecting neurodevelopment, immune activation, and synaptic transmission. PD patients with a long disease course have greater hemispheric asymmetry in neuronal epigenomes than those with a short disease course. Conclusions Hemispheric differences in DNA methylation patterns are prevalent in neurons and may affect the progression and symptoms of PD.

The transition of tau proteins from its soluble physiological conformation to the pathological aggregate forms found in Alzheimer's disease and related dementias, is poorly understood. Therefore, understanding the process that modulates the formation of toxic tau oligomers and their conversion to putative neuroprotective neurofibrillary tangles will lead to better therapeutic strategies. We previously identified that EFhd2 is associated with aggregated tau species in AD brains and the coiled-coil domain in EFhd2 mediates the interaction with tau. To further characterize the association between EFhd2 and tau, we examined whether EFhd2 could affect the liquid-liquid phase separation properties of tau under molecular crowding conditions. We demonstrate that EFhd2 alters tau liquid phase behavior in a calcium and coiled-coil domain dependent manner. Co-incubation of EFhd2 and tau in the absence of calcium leads to the formation of solid-like structures containing both proteins, while in the presence of calcium these two proteins phase separate together into liquid droplets. EFhd2's coiled-coil domain is necessary to alter tau's liquid phase separation, indicating that protein-protein interaction is required. The results demonstrate that EFhd2 affects the liquid-liquid phase separation of tau proteins , suggesting that EFhd2 modulates the structural dynamics of tau proteins.

To compare presentation of Alzheimer disease (AD) at the time of initial evaluation at a university specialty clinic across three ethnoracial groups in order to understand similarities and differences in the demographic, clinical, cognitive, psychiatric, and biologic features. Cross-sectional study. A total of 1,341 self-identified African American, Latino (primarily of Caribbean origin), and white non-Hispanic (“WNH”) subjects were recruited from primary care sites or by referral by primary care physicians. Demographic variables and age of onset of AD, as well as cognitive, functional, and mood impairments at the time of initial presentation and frequencies of apolipoprotein E genotypes, were compared across groups. Differences among ethnoracial groups were found for nearly all variables of interest. In particular, the largely immigrant Puerto Rican Latino group had an earlier age of onset of AD, more cognitive impairment, and greater severity of cognitive impairment at the time of initial evaluation in the setting of low average education and socioeconomic status. There was more depression in the Latinos compared with African Americans and WNHs. Greater severity of symptoms was not accounted for by a difference in lag time between onset of symptoms and initial evaluation. The apolipoprotein E-4 genotype was not associated with AD in the Latino cohort. Minority groups in Philadelphia, especially Latinos, exhibit a more severe profile of AD at the time of presentation than WNHs. Important potential confounds need to be considered and future research comparing immigrant and nonimmigrant Latino groups will be necessary to elucidate the highly significant differences reported.

The gastrointestinal tract may be a site of origin for α-synuclein pathology in idiopathic Parkinson’s disease (PD). Disruption of the autophagy-lysosome pathway (ALP) may contribute to α-synuclein aggregation. Here we examined epigenetic alterations in the ALP in the appendix by deep sequencing DNA methylation at 521 ALP genes. We identified aberrant methylation at 928 cytosines affecting 326 ALP genes in the appendix of individuals with PD and widespread hypermethylation that is also seen in the brain of individuals with PD. In mice, we find that DNA methylation changes at ALP genes induced by chronic gut inflammation are greatly exacerbated by α-synuclein pathology. DNA methylation changes at ALP genes induced by synucleinopathy are associated with the ALP abnormalities observed in the appendix of individuals with PD specifically involving lysosomal genes. Our work identifies epigenetic dysregulation of the ALP which may suggest a potential mechanism for accumulation of α-synuclein pathology in idiopathic PD. Dysfunction of the gastrointestinal system, and to the autophagy lysososmal pathway (ALP) have been reported in Parkinson’s disease. Here the authors report epigenetic disruption of ALP related genes in the appendix of individuals with Parkinson’s disease.

The polyunsaturated fatty acid (PUFA) synthases from deep-sea bacteria invariably contain multiple acyl carrier protein (ACP) domains in tandem. This conserved tandem arrangement has been implicated in both amplification of fatty acid production (additive effect) and in structural stabilization of the multidomain protein (synergistic effect). While the more accepted model is one in which domains act independently, recent reports suggest that ACP domains may form higher oligomers. Elucidating the three-dimensional structure of tandem arrangements may therefore give important insights into the functional relevance of these structures, and hence guide bioengineering strategies. In an effort to elucidate the three-dimensional structure of tandem repeats from deep-sea anaerobic bacteria, we have expressed and purified a fragment consisting of five tandem ACP domains from the PUFA synthase from Photobacterium profundum. Analysis of the tandem ACP fragment by analytical gel filtration chromatography showed a retention time suggestive of a multimeric protein. However, small angle X-ray scattering (SAXS) revealed that the multi-ACP fragment is an elongated monomer which does not form a globular unit. Stokes radii calculated from atomic monomeric SAXS models were comparable to those measured by analytical gel filtration chromatography, showing that in the gel filtration experiment, the molecular weight was overestimated due to the elongated protein shape. Thermal denaturation monitored by circular dichroism showed that unfolding of the tandem construct was not cooperative, and that the tandem arrangement did not stabilize the protein. Taken together, these data are consistent with an elongated beads-on-a-string arrangement of the tandem ACP domains in PUFA synthases, and speak against synergistic biocatalytic effects promoted by quaternary structuring. Thus, it is possible to envision bioengineering strategies which simply involve the artificial linking of multiple ACP domains for increasing the yield of fatty acids in bacterial cultures.

[...]the specificity of putative biomarkers has not reach a desirable level of certainty for the diagnosis of AD (Olsson et al., 2016). [...]due to the low invasiveness and promising results already obtained, most research efforts have been re-directed to develop selective molecules that facilitate the imaging of pathological proteins in living neurons and individuals. [...]this study demonstrated, for the first time, that pFTAA detects pathological tau in living neurons, becoming a valuable tool to assess compounds that target the aggregation and/or promote the disaggregation of pathological tau in cultured neurons, including iPSC-derived neurons from tauopathy patients. [...]studies that contribute to define the structural characteristics and temporal accumulation of pathological tau species and the cellular response to these species will contribute to the development of better diagnostic tools.

Aggregation of the protein tau is a pathological hallmark of Alzheimer's disease (AD) and related disorders. However, the molecular mechanisms that lead to tau protein aggregation are still unclear. Previously, we showed that EFhd2 protein is associated with pathological aggregated forms of tau in AD brain. Further, immuno-gold analyses of purified tau aggregates showed that EFhd2 co-localized with filamentous tau structures. We demonstrated that EFhd2's coiled-coil domain is required for its association with tau proteins. However, it is unknown the role that EFhd2 plays in tau aggregation. Here, we show that incubation of K19-tau with substoichiometric amount of EFhd2 promote the formation of amyloid structures . The result suggests that EFhd2 may play a role in the biogenesis of aggregated tau.