Abstract: Given improvements in viral vector design, production and efficiency of transduction in the central nervous system (CNS), as well as increased knowledge of neuropathological mechanisms in neurological disorders, success in treating a CNS disorder with gene transfer seems inevitable. Several different vector systems have been studied extensively and the adeno-associated viral vector system has been utilized in most early stage clinical trials in neurological disorders. Other vector systems, such as lentivirus, adenovirus, and herpes simplex virus are also viable vector platforms that should fill significant clinical niches based on their specific characteristics. In addition to the choice of the appropriate vector, the proper choice of transgene for the appropriate strategy to treat a neurological disorder is also critical. The example of glial cell line-derived neurotrophic factor ligands to treat Parkinson's disease is used to illustrate the importance of the interface between interpretation of pre-clinical data and consideration of the natural history of the disorder. This interface dictates the proper design of clinical trials that are capable of testing whether the treatment is actually successful. ... Read more

Abstract: Ghrelin is a recently identified gastric hormone that displays strong growth hormone (GH) releasing activity mediated by the GH secretagogue receptor (GHS-R). While this unique endogenous peptide participates in the regulation of energy homeostasis, increases food intake, and decreases energy expenditure, its ability to modulate immune regulation is another important feature. Here we discuss the effect of ghrelin on the immune system. Ghrelin was initially reported as an immune enhancing factor. More recently, however, the immunosuppressive effects of ghrelin have been found in several animal models including bowel disease, arthritis, and sepsis and endotoxemia. We recently demonstrated that exogenous administration of ghrelin suppressed experimental autoimmune encephalomyelitis, an animal model of multiple sclerosis in association with the reduction of pro-inflammatory cytokines in microglia. These results shed light on the new role of ghrelin in the regulation of disorders that pro-inflammatory cytokines contribute to the pathogenesis such as neuroinflammatory and mental diseases. ... Read more

Abstract: The APOE ε4 allele is associated with risk of late-onset Alzheimer's disease (AD). Longitudinal memory decline in asymptomatic APOE ε4 carriers shows greater acceleration compared with non-carriers, with a possible allele-dose effect, and begins prior to age 60. These results correlate with imaging and neuropathological studies that show AD-like changes at this age and collectively support the existence of a presymptomatic stage of AD. ... Read more

Abstract: The process of refolding or degrading misfolded proteins is the most important function of protein quality control (PQC) system. An imbalance between the capacity of PQC system and the quantity and severity of misfolded proteins may result in protein aggregate accumulation, which can ultimately contribute to a class of diseases referred to as conformational disorders. Numerous lines of evidence suggest that Ubiquilin 1 is an important component in PQC. Ubiquilin 1 has been indicated to be involved in the pathophysiology of neurodegenerative diseases and cancer. Here we review the evidence that Ubiquilin 1 is an important component of the PQC system and also review the role of Ubiquilin 1 in human diseases. ... Read more

Abstract: Alzheimer's disease (AD) is a progressive and degenerative disorder pathophysiologically characterized by the accumulation of beta-amyloid peptides (Aβ) in the brain. Aβ is indicated to be the primary agent in the pathogenesis of AD. Aβ is generated from the amyloid precursor protein (APP) via two proteolytic enzymes, β- and γ- secretases. α-secretase conducts an alternative proteolytic cleavage that prevents Aβ production and accumulation. Elevating levels of α-secretase cleavage, therefore, is a potential therapeutic strategy to treat AD. ... Read more

Abstract: Currently, we do not have effective therapies aimed at preventing or reversing axonal degeneration seen in peripheral neuropathies. Drug development programs should be aimed at understanding mechanisms of distal axonal degeneration and take into account the critical role Schwann cells play in axonal maintenance and nerve regeneration. ... Read more

Abstract: Neurodegenerative diseases, such as Huntington's disease, Parkinson's disease, Alzheimer's disease, and amyotrophic lateral sclerosis (ALS), are progressive neurological diseases that affect millions of people worldwide. Recent identification and advances in our understanding of multi-potent neural stem cells/progenitors in the mature CNS has raised the possibility that these discoveries can be translated into an effective therapy for degenerative neurological disease. ... Read more

Abstract: Molecular Trojan horses are genetically engineered proteins that cross the blood-brain barrier (BBB) via endogenous receptor-mediated transport processes. Molecular Trojan horses provide a brain drug targeting technology that allows for the non-invasive delivery of large molecule therapeutics to the human brain. The development of BBB drug targeting technology is an arcane area of discovery medicine that suffers from chronic under-development. ... Read more

Abstract: As with many other molecular agents that are involved in multiple aspects of cellular processes, E2F1 plays a dual role of cellular proliferation and apoptosis. How to take advantage of the apoptosis induction and sensitization properties of E2F1 for therapeutic purposes while minimizing its other properties has a significant bearing on how to turn a functionally complex molecule such as E2F1 into a drug target. ... Read more

Abstract: In addition to the immune system, apoptosis plays a role in the nervous system. An excessive number of cells are generated during embryogenesis and only neurons that make the correct connections at the right time survive. But then, these surviving neurons do not divide and they need to make it through the entire life of the organism and cannot be replaced once they are dead. The control over death and survival is therefore vitally important. ... Read more