Current Enzyme Inhibition (v.9, #1)
Preface by D. Hadjipavlou-Litina (i-).
Editorial (Hot Topic: Therapeutic Targets in Neurodegenerative Diseases) by Jungsu Kim, Jason L. Eriksen (1-2).
BACE1: Expression, Regulation, and Therapeutic Potential of the Major Alzheimerµs Disease Beta-Secretase by Christopher J. Holler, Michael P. Murphy (3-14).
The number of individuals afflicted by Alzheimer's disease (AD) worldwide is rapidly rising and we, as a society,are approaching a critical junction in the development of new therapeutics aimed at slowing or preventing the onset ofthis devastating neurodegenerative disease. The prevailing theory in the field pinpoints the amyloid β peptide (Aβ) as thecausal agent of the disease and thus strategies that target the production, deposition, and clearance of Aβ in the brain continueto be at the forefront of therapeutic interventions. Aβ is produced through a series of proteolytic cleavage events,with β-secretase (BACE1) being the rate-limiting enzymatic activity needed to begin the liberation of the Aβ peptide fromthe larger amyloid precursor protein (APP). As such, BACE1 itself has become a prime therapeutic target for AD. Still,over ten years after its discovery, only a handful of compounds targeting BACE1 have reached clinical trial, indicatingthat complex challenges continue to persist. This short review will focus on the cellular and molecular characteristics ofBACE1, its role in APP processing and in AD, and its potential as a therapeutic target for AD.
Diverse Functions of ? -secretase: Releasing Signaling Fragments and Deleterious Molecules by Sun-Ho Han, Chaeyoung Kim, Inhee Mook-Jung (15-27).
?-secretase is a pleiotropic intramembrane-cleaving protease. It is a multiprotein complex that comprises presnilin(PS), nicastrin (NCT), presnilin enhancer-2 (Pen-2), and anterior pharynx-defective-1 (Aph-1)-all of which are essentialfor its proteolytic activity. Promiscuously diverse substrates are susceptible to cleavage by ?-secretase, of whichamyloid precursor protein (APP) and notch are the well-characterized substrates. Specifically, APP processing by ? -secretase has garnered much attention, because the generation of amyloidogenic amyloid ? peptide (A?) is the hallmark ofthe pathogenesis of Alzheimer's disease (AD). Thus, the regulatory mechanisms and substrate specificities of ?-secretaseproteolytic activity have been studied extensively as therapeutic targets of AD. Further, the processing of other substrateshas broad biological implications, releasing an intracellular domain that functions as a signaling molecule. Hence, ? -secretase regulates many physiological functions and pathologies.We summarize the current literatures on ?-secretase, including its assembly and substrates. Its diverse substrates and thedownstream events that are initiated by the release of the intracellular domains of substrates after ?-secretase cleavage arediscussed, as is their significance under normal and aberrant physiological conditions. Further, the regulation of ? -secretase activity is broached to yield insights into using this promiscuous enzyme to develop therapeutic agents for AD.
Defects in RNA Metabolism links FTD and ALS Pathogenesis: TDP-43, FUS, and C9orf72 by Qiudong Deng, Termpanit Chalermpalanupap, Thomas Kukar (28-40).
Increasing evidence supports the idea that frontotemporal dementia (FTD) and amyotrophic lateral sclerosis(ALS) share underlying causes and lie on opposite ends of a disease spectrum that leads to these disorders. The discoveryof two different RNA binding proteins, TDP-43 and FUS/TLS, as common neuronal inclusions in FTD and ALS patientshas strengthened this connection. Subsequent identification of mutations in TDP-43 and FUS that cause ALS, and FTD inrare cases, provides additional linkage between these diseases. Furthermore, autosomal dominant forms of FTD, ALS, or acombined phenotype can occur in the same family. Genetic studies have linked some of these cases to chromosome 9p21and are known as c9FTD/ALS. Recently, an expanded GGGGCC hexanucleotide repeat in the C9ORF72 gene has beenidentified in c9FTD/ALS cases as well as sporadic forms of both diseases. Preliminary data suggest that the increased nucleotiderepeats in C9ORF72 lead to RNA inclusions or foci in the nucleus of affected cells. Analogous to other repeatdisorders such as myotonic dystrophy, expanded repeats in C9ORF72 may cause disease pathogenesis by sequesteringRNA binding proteins and/or perturbing the splicing and regulation of key proteins regulating neuronal health and survival.Intriguingly, TDP-43 and FUS/TLS play fundamental roles in RNA regulation and splicing, and their mutationleads to dysfunctional regulation of their targets in model systems. Finally, defects in RNA splicing have been reported insporadic ALS and a number of other genes involved in RNA metabolism (ANG, SETX, TAF15, ELP3, ATXN2) are associatedwith ALS. Based on these recent findings, we propose that defects in RNA metabolism are a common pathway linkingFTD and ALS, and are responsible for disease pathogenesis in a significant portion of cases. Further research to testthis hypothesis and determine if these proteins function within common biological pathways and share similar pathogenicmechanisms will ultimately open up new routes of therapy for these devastating disorders.
Reconstructing the Hsp90/Tau Machine by Umesh K. Jinwal, John Koren III, Chad A. Dickey (41-45).
Imbalanced protein load within cells is a critical aspect for most diseases of aging. In particular, the accumulationof proteins into neurotoxic aggregates is a common thread for a host of neurodegenerative diseases. Recent workdemonstrates that age-related changes to the cellular chaperone repertoire contribute to abnormal buildup of the microtubule-associated protein tau that accumulates in a group of diseases termed tauopathies, the most common being Alzheimer'sdisease (AD). The Hsp90 co-chaperone repertoire has diverse effects on tau stability; some co-chaperones stabilizetau while others facilitate its clearance. We propose that each of these proteins may be novel therapeutic targets.While targeting Hsp90 directly may be deleterious at the organismal level, perhaps targeting individual co-chaperone activitieswill be more tolerable.
Therapeutic Targets in the Ubiquitin-proteasome System for Alzheimer's Disease by Jason L. Eriksen (46-54).
The appearance of protein aggregates is a common pathological hallmark that is associated with Alzheimer'sdisease and other major neurodegenerative disorders. Misfolded and damaged proteins that accumulate in neurodegenerativedisease can be cleared through the ubiquitin proteasome system (UPS), a highly regulated pathway whose properfunction is of paramount importance in the selective degradation of protein. Studies of the UPS have shown that alterationsin the activity of this complex system may be contributors in the etiology of specific neurodegenerative disorders.Studies of familial genetic mutations and through experimental manipulation have suggested that a failure to clear toxicproteins through the UPS may exert important effect on the progression of these disorders; in addition, the accumulationof hallmark proteins themselves may in turn impair clearance by this pathway. This review will discuss recent observationsindicating that alterations in the function and efficiency of the UPS are contributors in pathogenesis of Alzheimer'sdisease, and discuss whether modulation of the UPS may be an appropriate therapeutic target in Alzheimer's disease andsimilar neurological disorders.
Role of Autophagy in Alzheimerµs Disease by Jaekwang Kim, Hyejin Yoon, Jungsu Kim (55-66).
Autophagy is a tightly regulated lysosomal degradation/recycling pathway, critical for cellular homeostasis,such as neuronal survival and death. Impaired autophagic function has been reported in several neurodegenerative diseases,such as Parkinson's, Huntington's and Alzheimer's disease (AD). AD is the most common cause of dementia in theelderly and it is characterized by progressive memory loss and cognitive decline along with synaptic dysfunction. Accumulationsof amyloid ? (A?) and tau proteins are two major neuropathological hallmarks of AD. In addition, accumulationof autophagic vacuoles and other autophagic pathology are evident in dystrophic neurites of AD brains. A series of studieshas suggested that autophagy is involved in metabolism of A? and tau. Moreover, presenilin (PS), a core subunit of ?-secretase complex, has been demonstrated to play an important role in autophagy at the level of lysosomal proteolysis. Inspite of several therapeutic approaches through modulation of autophagic pathway, inconsistent results among studieshave made it difficult to determine whether autophagy induction will be beneficial or detrimental for AD pathogenesis.Therefore, roles of autophagy in AD need to be further investigated to develop therapeutic strategies in the future.
Trisubstituted Phenolic Compounds as Inhibitors of Acetylcholinesterase and Amyloid Beta Aggregate Formation by Caroline M. Peckels, Nathan S. Alexander, Gina N. Wilson, Joel M. Karty, Kathryn M. Matera (67-74).
Neurophysiological indicators of Alzheimer's disease include the presence of aggregated amyloid-beta (Aβ) peptide plaques and low levels of the neurotransmitter, acetylcholine, resulting in cognitive impairment.Acetylcholinesterase has been implicated in not only the aggregation of extracellular Aβ peptides through the enzyme'speripheral anionic site, but also the hydrolysis of acetylcholine at its catalytic active site. Two components in a methanolicextract of black walnuts (Juglians nigra), gallic and ellagic acids, were found to prevent aggregation of Aβ peptides in thepresence of acetylcholinesterase and to disaggregate previously formed oligomers. In addition, both compounds inhibitedacetylcholinesterase activity, thus retaining higher acetylcholine concentrations. Analysis of phenolic structures related togallic acid indicated that 1,3,5-trisubstituted phenolic rings conferred these inhibitory effects on acetylcholinesterase, andthus may provide a structural model on which to design dual inhibitors for both acetylcholinesterase catalytic activity andAβ aggregation and disaggregation.
Inhibition of Candida rugosa Lipase by Secondary Metabolites Extracts of Three Algerian Plants and their Antioxydant Activities by K. Benarous, A. Djeridane, A. Kameli, M. Yousfi (75-82).
Lipase inhibitors have generated a great interest because they could help in the prevention or the therapy oflipase?related diseases. Therefore, the aim of this work was to evaluate the inhibitory effect of secondary metabolitesextracts such as phenolic compounds and saponins of three Algerian medicinal plants: Achillea santolina, Inonotushispidus and Zizyphus lotus, indeed their antiradicalaire activity using DPPH. (1, 1?diphenyl?2?picryl?hydrazyl). Thephenolic extracts have shown a strong antiradicalaire activity than the saponin extracts with EC50 values ranged from 6 to11 ?g/ml and from 51 to 82 ?g/ml, respectively. The enzymatic inhibition produced by these plant extracts is describedhere for the first time. The results have shown that the phenolic extracts are more potent than the saponin extracts with Kivalues ranged from 0.011 mg/ml to 0.027 mg/ml for phenolic extracts, and ranged from 0.071 mg/ml to 0.69 mg/ml forsaponin extracts. The nature, mechanism and possible physiological relevance of lipase inhibition by extract componentsare discussed.