Mammalian-Specific Central Myelin Protein Opalin Is Redundant for Normal Myelination: Structural and Behavioral Assessments

Besides its insulinotropic actions on pancreatic β cells, neuroprotective activities of glucagon-like peptide-1 (GLP-1) have attracted attention. The efficacy of a GLP-1 receptor (GLP-1R) agonist exendin-4 (Ex-4) for functional repair after sciatic nerve injury and amelioration of diabetic peripheral neuropathy (DPN) has been reported; however, the underlying mechanisms remain unclear. In this study, the bioactivities of Ex-4 on immortalized adult rat Schwann cells IFRS1 and adult rat dorsal root ganglion (DRG) neuron–IFRS1 co-culture system were investigated. Localization of GLP-1R in both DRG neurons and IFRS1 cells were confirmed using knockout-validated monoclonal Mab7F38 antibody. Treatment with 100 nM Ex-4 significantly enhanced survival/proliferation and migration of IFRS1 cells, as well as stimulated the movement of IFRS1 cells toward neurites emerging from DRG neuron cell bodies in the co-culture with the upregulation of myelin protein 22 and myelin protein zero. Because Ex-4 induced phosphorylation of serine/threonine-specific protein kinase AKT in these cells and its effects on DRG neurons and IFRS1 cells were attenuated by phosphatidyl inositol-3′-phosphate-kinase (PI3K) inhibitor LY294002, Ex-4 might act on both cells to activate PI3K/AKT signaling pathway, thereby promoting myelination in the co-culture. These findings imply the potential efficacy of Ex-4 toward DPN and other peripheral nerve lesions.

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Protein farnesylation is upregulated in Alzheimer’s human brains and neuron-specific suppression of farnesyltransferase mitigates pathogenic processes in Alzheimer’s model mice

Acta Neuropathologica Communications ◽

10.1186/s40478-021-01231-5 ◽

2021 ◽

Vol 9 (1) ◽

Author(s):

Angela Jeong ◽

Shaowu Cheng ◽

Rui Zhong ◽

David A. Bennett ◽

Martin O. Bergö ◽

...

Keyword(s):

Cognitive Impairment ◽

Small Gtpases ◽

Specific Role ◽

Postmortem Brain ◽

Effective Prevention ◽

Postmortem Brain Tissue ◽

Mtorc1 Signaling ◽

Behavioral Assessments ◽

Human Brains

AbstractThe pathogenic mechanisms underlying the development of Alzheimer’s disease (AD) remain elusive and to date there are no effective prevention or treatment for AD. Farnesyltransferase (FT) catalyzes a key posttranslational modification process called farnesylation, in which the isoprenoid farnesyl pyrophosphate is attached to target proteins, facilitating their membrane localization and their interactions with downstream effectors. Farnesylated proteins, including the Ras superfamily of small GTPases, are involved in regulating diverse physiological and pathological processes. Emerging evidence suggests that isoprenoids and farnesylated proteins may play an important role in the pathogenesis of AD. However, the dynamics of FT and protein farnesylation in human brains and the specific role of neuronal FT in the pathogenic progression of AD are not known. Here, using postmortem brain tissue from individuals with no cognitive impairment (NCI), mild cognitive impairment (MCI), or Alzheimer’s dementia, we found that the levels of FT and membrane-associated H-Ras, an exclusively farnesylated protein, and its downstream effector ERK were markedly increased in AD and MCI compared with NCI. To elucidate the specific role of neuronal FT in AD pathogenesis, we generated the transgenic AD model APP/PS1 mice with forebrain neuron-specific FT knockout, followed by a battery of behavioral assessments, biochemical assays, and unbiased transcriptomic analysis. Our results showed that the neuronal FT deletion mitigates memory impairment and amyloid neuropathology in APP/PS1 mice through suppressing amyloid generation and reversing the pathogenic hyperactivation of mTORC1 signaling. These findings suggest that aberrant upregulation of protein farnesylation is an early driving force in the pathogenic cascade of AD and that targeting FT or its downstream signaling pathways presents a viable therapeutic strategy against AD.

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Behavior assessment and applications for BRD diagnosis: preweaned dairy calves

Animal Health Research Reviews ◽

10.1017/s1466252320000213 ◽

2020 ◽

pp. 1-4

Author(s):

Catie Cramer ◽

Theresa L. Ollivett

Keyword(s):

Clinical Signs ◽

Sickness Behavior ◽

Behavioral Changes ◽

Dairy Calves ◽

Detection Methods ◽

Disease Detection ◽

Test Characteristics ◽

Behavioral Studies ◽

Detection Program ◽

Behavioral Assessments

Abstract Bovine respiratory disease (BRD) is an important disease in dairy calves due to its long-lasting effects. Early identification results in better outcomes for the animal, but producers struggle to identify all calves with BRD. Sickness behavior, or the behavioral changes that accompany illness, has been investigated for its usefulness as a disease detection tool. Behavioral changes associated with BRD include decreased milk intake and drinking speed, depressed attitude, and less likelihood of approaching a novel object or stationary human. Behavioral measurements are useful, as they can be collected automatically or with little financial input. However, one limitation of many BRD behavioral studies includes the use of either lung auscultation or clinical signs as reference methods, which are imperfect. Additionally, external factors may influence the expression of sickness behavior, which can affect if and when behavior can be used to identify calves with BRD. Behavioral measures available to detect BRD lack adequate sensitivity and specificity to be the sole means of disease detection, especially when detection tools, such as calf lung ultrasound, have better test characteristics. However, using behavioral assessments in addition to other detection methods can allow for a robust BRD detection program that can ameliorate the consequences of BRD.

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