Activity

Myosins generate force and motion by precisely coordinating their mechanical and chemical cycles, but the nature and timing of this coordination remains controversial. We utilized a FRET approach to examine the kinetics of structural changes in the force-generating lever arm in myosin V. We directly compared the FRET results with single-molecule mechanical events examined by optical trapping. Guggulsterone E&Z We introduced a mutation (S217A) in the conserved switch I region of the active site to examine how myosin couples structural changes in the actin- and nucleotide-binding regions with force generation. Specifically, S217A enhanced the maximum rate of lever arm priming (recovery stroke) while slowing ATP hydrolysis, demonstrating that it uncouples these two steps. We determined that the mutation dramatically slows both actin-induced rotation of the lever arm (power stroke) and phosphate release (≥10-fold), whereas our simulations suggest that the maximum rate of both steps is unchanged by the mutation. Time-resolved FRET revealed that the structure of the pre- and post-power stroke conformations and mole fractions of these conformations were not altered by the mutation. Optical trapping results demonstrated that S217A does not dramatically alter unitary displacements or slow the working stroke rate constant, consistent with the mutation disrupting an actin-induced conformational change prior to the power stroke. We propose that communication between the actin- and nucleotide-binding regions of myosin assures a proper actin-binding interface and active site have formed before producing a power stroke. Variability in this coupling is likely crucial for mediating motor-based functions such as muscle contraction and intracellular transport.Here I present the scientific rationale and implementation strategies for elimination of early-onset neurodegenerative disorders (EONDD) from future generations, and for risk reduction and treatments for the more common late-onset neurodegenerative disorders (LONDD). Young adults with a family history of an EONDD should be educated on the genetics and familial burden of EONDD. They can then be genotyped and, if positive for the mutation, counseled as to how they can ensure that none of their children will be affected by choosing either adoption or in vitro fertilization and preimplantation genetic testing. LONDD risk reduction will require education of physicians and patients on the benefits of regular intermittent bioenergetic and cognitive challenges (exercise, intermittent fasting, intellectual challenges and social engagement) for brain health, and on specific risk-reduction regimens. Regulations will be required to counteract the disease-promoting mercenary practices of the processed food and pharmaceutical industries. Clinical trials of pharmacological interventions should shift to small trials of agents that substantially mimic mechanisms of action of exercise and intermittent fasting to bolster neuronal bioenergetics and stress resistance.The 1102-amino-acid activity-dependent neuroprotective protein (ADNP) was originally discovered by expression cloning through the immunological identification of its 8-amino-acid sequence NAPVSIPQ (NAP), constituting the smallest active neuroprotective fragment of the protein. ADNP expression is essential for brain formation and cognitive function and is dysregulated in a variety of neurodegenerative diseases (Alzheimer’s disease, Parkinson’s disease, and schizophrenia). ADNP has been found to be mutated in autism, with an estimated prevalence of 0.17% (together, these autism cases now constitute ADNP syndrome cases) and our recent results showed somatic mutations in ADNP in Alzheimer’s disease brains correlating with tauopathy. Furthermore, Adnp haploinsufficiency in mice causes an age-dependent reduction in cognitive functions coupled with tauopathy-like features such as an increased formation of tangle-like structures, defective axonal transport, and Tau hyperphosphorylation. ADNP and its derived peptides,4-MT binding isoform (Tau4R) and PSP enriched in Tau4R pathology). We reveal the direct effect of truncated ADNPs (resulting from de novo autism and newly discovered Alzheimer’s disease-related somatic mutations) on MT dynamics. We show that the peptide SKIP affects MT dynamics and MT-Tau association. Since MT impairment is linked with neurodegenerative and neurodevelopmental conditions, the current study implicates a paucity/dysregulation of MT-interacting endogenous proteins, like ADNP, as a contributing mechanism and provides hope for NAP and SKIP as MT-modulating drug candidates.Neurodegenerative diseases are currently some of the most debilitating and incurable illness, including highly prevalent disorders, such as Alzheimer’s and Parkinson’s disease. Despite impressive advances in understanding the molecular basis of neurodegenerative diseases, several clinical trials have failed in identifying drugs that successfully delay or stop disease progression. New targets are likely necessary to successfully combat these devastating diseases. In this chapter, we review the evidence indicating that impairment in the cellular energy machinery in the form of mitochondrial damage and dysfunction may be at the root of neurodegeneration. We also propose that transplant of functional isolated mitochondria may overcome the energetic damage and delay the progression of neurodegenerative diseases.After Alzheimer’s disease, Parkinson’s disease is the most frequent neurodegenerative disorder. Although numerous treatments have been developed to control the disease symptomatology, with some successes, an efficacious therapy affecting the causes of PD is still a goal to pursue. The genetic evidence and the identification of α-synuclein as the main component of intracellular Lewy bodies, the neuropathological hallmark of PD and related disorders, have changed the approach to these disorders. More recently, the detrimental role of α-synuclein has been further extended to explain the wide spread of cerebral pathology through its oligomers. To emphasize the central pathogenic role of these soluble aggregates, we have defined synucleinopathies and other neurodegenerative disorders associated with protein misfolding as oligomeropathies. Another common element in the pathogenesis of oligomeropathies is the role played by inflammation, both at the peripheral and cerebral levels. In the brain parenchyma, inflammaton contrast, astrocyte activation was attenuated and these cells appeared damaged when chronic inflammation was combined with α-synuclein exposure. This evidence might indicate a more specific anti-inflammatory strategy rather than the generic anti-inflammatory treatment.Alzheimer’s disease (AD) is the leading cause of dementia and sixth cause of death in elderly adults. AD poses a huge economic burden on society and constitutes an unprecedented challenge for caregivers and families affected. Aging of the population is projected to drastically aggravate the situation in the near future. To date, no therapy is available to prevent or ameliorate the disease. Moreover, several clinical trials for promising therapeutic agents have failed. Lack of supporting biomarker data for pre-symptomatic enrollment and inaccurate stratification of patients based on genetic heterogeneity appear to be contributing factors to this lack of success. Recently, the treatment of cancer has seen enormous advances based on the personalized genetics and biomarkers of the individual patient, forming the foundation of precision medicine for cancer. Likewise, technological progress in AD biomarker research promises the availability of reliable assays for pathology staging on a routine basis relatively soon. Moreover, tremendous achievements in AD genetics and high-throughput genotyping technology allow identification of predisposing risk alleles accurately and on a large scale. Finally, availability of electronic health records (EHR) promises the opportunity to integrate biomarker, genomic and clinical data efficiently. Together, these advances will form the basis of precision medicine for AD.New neurons are generated in the dentate gyrus of the adult brain throughout life. They incorporate in the granular cell layer of the dentate gyrus and integrate in the hippocampal circuitry. Increasing evidence suggests that new neurons play a role in learning and memory. In turn, a large body of evidence suggests that neurogenesis is impaired in Alzheimer’s disease, contributing to memory deficits characterizing the disease. We outline here current knowledge about the biology of adult hippocampal neurogenesis and its function in learning and memory. In addition, we discuss evidence that neurogenesis is dysfunctional in Alzheimer’s disease, address the controversy in the literature concerning the persistence of hippocampal neurogenesis in the adult and aging human brain, and evaluate the therapeutic potential of neurogenesis-based drug development for the treatment of cognitive deficits in Alzheimer’s disease.Alzheimer’s disease (AD) is a complex disease of the brain. Despite over 100 years of basic and clinical research, significantly intensified in the last three decades, the exact cause of this neurodegeneration is still an enigma. Based on neuroanatomical, experimental, and clinical findings, a series of hypotheses on AD pathogenesis have evolved. Among them, the “amyloid cascade hypothesis” has been most prominent. Clinical efforts targeting the biochemistry of amyloid β-protein (Aβ) as causal therapy have all failed so far, which may mean that the pathogenic mechanism of AD is less straightforward than initially thought. While there was good scientific reason to support this hypothesis before, the exclusive concentration on it may have impeded a more objective look and prevented the pursuit of alternative approaches to decipher the cause of AD. Here, a few key hypotheses of AD are summarized, and it is proposed that our view of the cause (or causes) of this detrimental disease be widened. This includes looking back, reactivating, and revisiting findings that were ignored over the last decades. Alternative and amyloid-independent ways to explain AD pathogenesis should receive more attention and are appearing.Recent data establish multiple defects in endocytic functions as early events initiating various neurodegenerative disorders, including Alzheimer’s disease (AD). The genetic landscape resulting from genome-wide association studies (GWAS) reveals changes in post-endocytic trafficking of amyloid precursor protein (APP) in neurons leading to an increase in amyloidogenic processing, deficits in amyloid beta (Aβ) clearance, increases in intracellular Aβ, and other endosomal pathogenic phenotypes. Multiple genetic factors regulate each segment of endosomal and post-endosomal trafficking. Intriguingly, several studies indicate endosomal dysfunctions preceding Aβ pathology and tau phosphorylation. In this chapter we highlight the role of various GWAS-identified endosomal and post-endosomal gene products in initiating AD pathologies. We also summarize the functions of various genetic modifiers of post-endocytic trafficking of APP that may work as targets for therapeutic intervention in AD.