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Role of Environmental Toxicants and Inflammation in Parkinson’s Disease
Published in Abhai Kumar, Debasis Bagchi, Antioxidants and Functional Foods for Neurodegenerative Disorders, 2021
Biddut Deb Nath, Dipti Debnath, Rokeya Pervin, Md. Akil Hossain
Moreover, in a dopaminergic cell, line silencing LAMP2A action boosted a-synuclein’s half-life and lowered chaperone-mediated autophagy. Modified processing of α-syn may also be caused by mutation/damage of the ATPase (ATP13A2) membrane protein of lysosome, which is influenced in a type of hereditary PD.101 In dopaminergic cells, treatment with toxins triggered decline of lysosomes secondary to the onset of oxidative stress, which resulted in cellular deterioration and autophagosomal aggregation. Genetic and pharmacological treatments that augmented lysosomal development have attenuated the toxic effects of the MPTP. Changes in mitophagy and autophagy often emerge in reaction to 6-OHDA-induced nigral neuronal damage.102 In PD, the thread advocating neuronal failure participation arises from Gaucher disease, a lysosomal storage condition triggered by GBA gene mutations. This contributes to a deficit of the enzyme of lysosome GCase that acts as a catalyst in the metabolism of the sphingolipid glucosylceramide to ceramide. A GCase deprivation has recently been identified in the SN of patients with PD and GBA mutations but also, most notably, among those with irregular PD.103 As not all people with GBA mutations progress to PD, this is likely to result in elevated vulnerability to certain pathogenic factors, such as oxidative stress arising from impaired mitochondrial activity and α-syn aggregation.104
The Role of Biological Lipids in Skin Conditioning
Published in Randy Schueller, Perry Romanowski, Conditioning Agents for Hair and Skin, 2020
Proof of the role of intercellular beta-glucocerebrosidase in this process has been provided by the use of both enzyme-specific inhibitors (conduritols) and a transgenic murine model (40,41). In both approaches, lack of enzyme activity leads to a barrier abnormality, which appears to be attributable to accumulation of glucosylceramides (not depletion of ceramides). This biochemical change is accompanied by the persistence throughout the stratum corneum interstices of immature membrane structures. Interestingly, these immature or incompletely processed membrane structures also appear in a subgroup of Gaucher disease (type II), which is characterized by drastically reduced enzyme levels and ichthyosiform skin lesions (42). Such immature, glycosylated membrane structures, although inadequate to meet the demands of terrestrial life, nevertheless appear to suffice in mucosal epithelia (43,44) and in the stratum corneum of marine cetaceans, which both display a high glycosylceramide-to-ceramide ratio (45). Pertinently, endogenous 13-giucosidase levels are reduced in oral mucosa (46). Thus, the persistence of glucosylceramides may indicate less stringent barrier requirements in these locales and/or additional functions of glucosylceramides unique to these tissues.
Biocatalyzed Synthesis of Antidiabetic Drugs
Published in Peter Grunwald, Pharmaceutical Biocatalysis, 2019
Interestingly, by following a similar strategy starting from N-butylglucamine 119, it was possible to produce Miglustat (N-butyl-deoxynojirimycin 120, Fig. 11.41, marketed as Zavesca™), another glycosidase inhibitor acting as a pharmacological chaperone for brain glucosylceramide synthase, therefore avoiding the accumulation of glucosylceramide leading to Gaucher’s disease (Yu et al., 2007). Synthesis of Miglustat 120 via regioselective biooxidation of N-butylglucamine 119.
Glucocerebrosidase as a therapeutic target for Parkinson’s disease
Published in Expert Opinion on Therapeutic Targets, 2020
Yu Chen, Richard Sam, Pankaj Sharma, Lu Chen, Jenny Do, Ellen Sidransky
After several decades of preclinical work, the first effective therapy for Gaucher disease, enzyme replacement therapy (ERT) became available in 1991 [15]. While initially a placental derived product, a recombinant form of the enzyme, imiglucerase was soon developed, and currently there are several approved forms of the recombinant enzyme. Each successfully reverses the anemia, thrombocytopenia and hepatosplenomegaly associated with Gaucher disease, remarkably improving the current clinical course for patients with Gaucher disease. However, ERT is a treatment, but not a cure, and it requires regular intravenous infusions of the costly enzyme. Furthermore, it does not cross the blood-brain -barrier (BBB), and thus is not effective in treating manifestations specifically encountered in patients with neuronopathic forms of the disease. A second therapeutic approach is substrate reduction therapy (SRT) targeting glucosylceramide synthesis, which also effectively reduces non-neurologic manifestations of Gaucher disease. However, since both ERT and SRT are extremely expensive and do not reverse neuronopathic Gaucher disease, there remains a strong rationale for developing new therapeutic strategies for patients with Gaucher disease.
An update on gene therapy for lysosomal storage disorders
Published in Expert Opinion on Biological Therapy, 2019
Murtaza S. Nagree, Simone Scalia, William M. McKillop, Jeffrey A. Medin
Outside of these two clinical trials, LV-based, HSC-directed, gene therapy is being investigated in animal models of other LSDs as well. While an early clinical attempt using γ-RV failed to generate long-term marking and engraftment of transduced CD34+ cells for the treatment of Gaucher disease [48], recent work using a recombinant LV as the delivery vehicle was successful in raising glucosylceramidase activity, clearing glucosylceramide buildup, and stopping the progression of Gaucher pathology in a mouse model of Type I Gaucher disease [49]. AVROBIO, Inc. has received a No Objection response from Health Canada to launch a phase I clinical trial based on this approach (AVRO-RD-02–201). This trial is expected to open in 2019.
Ceramide pathway: A novel approach to cancer chemotherapy
Published in Egyptian Journal of Basic and Applied Sciences, 2018
Mahdi Mashhadi Akbar Boojar, Masoud Mashhadi Akbar Boojar, Sepide Golmohammad
The entrance of ceramide to the Golgi apparatus is considered as the gateway for the manufacture of glycosphingolipids [29]. In this case, the first step is the addition of glucose from UDP-glucose to ceramide by glucosylceramide synthase enzyme and glucosylated ceramide production [17]. In the next steps, various products of glycosphingolipids, which are mainly structural and cellular markers, are derived from this mediator or additional glucosylated ceramides in the inverse pathway of the reaction are converted by cerebrosidase into its constructive ceramide [3]. Thus, the activity of glucosylceramide synthase is a cell rescuer from ceramide-induced apoptosis and a way to chemotherapy resistance [38].