Neurodegeneration: From cellular concepts to clinical applications

Katsnelson, Alla; Strooper, Bart De; Zoghbi, Huda Y.

doi:10.1126/scitranslmed.aal2074

Cited by 89 publications

(50 citation statements)

References 31 publications

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“…Understanding and combatting neurodegeneration is currently of paramount importance to medicine and human health, and animal models have proven to be extremely valuable in elucidating underlying genetic and molecular mechanisms [19,47]. The climbing assay is a standard test of neurodegeneration in the Drosophila model system and can be performed by novice students at minimal cost [28,29].…”

Section: Implementing the Curementioning

confidence: 99%

A course-based undergraduate research experience examining neurodegeneration in Drosophila melanogaster teaches students to think, communicate, and perform like scientists

Delventhal

Steinhauer

2020

PLoS ONE

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As educators strive to incorporate more active learning and inquiry-driven exercises into STEM curricula, Course-based Undergraduate Research Experiences (CUREs) are becoming more common in undergraduate laboratory courses. Here we detail a CURE developed in an upper-level undergraduate genetics course at Yeshiva University, centered on the Drosophila melanogaster ortholog of the human neurodegeneration locus PLA2G6/PARK14. Drosophila PLA2G6 mutants exhibit symptoms of neurodegeneration, such as attenuated lifespan and decreased climbing ability with age, which can be replicated by neuron-specific knockdown of PLA2G6. To ask whether the neurodegeneration phenotype could be caused by loss of PLA2G6 in specific neuronal subtypes, students used GAL4-UAS to perform RNAi knockdown of PLA2G6 in subsets of neurons in the Drosophila central nervous system and measured age-dependent climbing ability. We organized our learning objectives for the CURE into three broad goals of having students think, communicate, and perform like scientists. To assess how well students achieved these goals, we developed a detailed rubric to analyze written lab reports, administered pre-and post-course surveys, and solicited written feedback. We observed striking gains related to all three learning goals, and students reported a high degree of satisfaction. We also observed significantly improved understanding of the scientific method by students in the CURE as compared to the prior year's non-CURE genetics lab students. Thus, this CURE can serve as a template to successfully engage students in novel research, improve understanding of the scientific process, and expose students to the use of Drosophila as a model for human neurodegenerative disease.

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Section: Implementing the Curementioning

confidence: 99%

A course-based undergraduate research experience examining neurodegeneration in Drosophila melanogaster teaches students to think, communicate, and perform like scientists

Delventhal

Steinhauer

2020

PLoS ONE

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“…The pathogenesis of neurodegenerative diseases (ND) is characterized by the aggregation of specific proteins in intracellular inclusions or extracellular aggregates. The hallmark protein tends to be different for each disease [1] but the overlap is striking (Table 1). Amyloid-beta plaques (Aβ) and tau tangles characterize Alzheimer's disease (AD) affected brains, and tau, but not Aβ, is also aggregated in frontotemporal dementia (FTD).…”

Section: Introductionmentioning

confidence: 99%

Polygenic Risk Scores in Neurodegenerative Diseases: a Review

et al. 2019

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Purpose of the Review This review summarizes the current state of the art of polygenic risk scores (PRSs) in the assessment of risk for neurodegenerative diseases. Recent Findings Polygenic risk scores have been used to identify the shared genetic architecture between comorbid complex traits, disease presentations, and disease endophenotypes. Summary The pathological and symptomatologic overlap between neurodegenerative diseases is strikingly high. In some cases, the diagnostic decision is arbitrary depending on the first appearance of symptomatology. Genetic studies have demonstrated that the genetic architecture of each of these diseases is different, but has a high degree of overlap. The creation of polygenic risk scores has allowed a more accurate calculation of this overlap. However, the power of the PRS is dependent on the power of the genome-wide association studies (GWAS) used to describe the genetic architecture. Even though not all neurodegenerative disease GWAS have the same sample size, and thus the same power, the use of polygenic risk scores has been successful in demonstrating the genetic overlap that has been observed phenotypically.

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“…The culture model we describe here may thus be a useful new tool to identify these largely unknown details. This simple neuronal culture model could additionally be a useful tool to identify new therapeutic targets and agents so desperately needed by the growing population of AD patients [96]. While cell culture models may never be able to generate the full complexity of AD disease phenotypes, they are likely to be important for solving many pieces of the puzzle and the exact pathogenic role of Aβ accumulation within or around human neurons seems like an important step forward.…”

Section: Discussionmentioning

confidence: 99%

A human embryonic stem cell model of Aβ-dependent chronic progressive neurodegeneration

Ubina

Magallanes

Srivastava

et al. 2018

Preprint

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32 We describe construction and phenotypic analysis of a human embryonic stem cell model of 33 progressive A-dependent neurodegeneration (ND) with potential relevance to Alzheimer's 34 disease (AD). We modified one allele of the normal APP locus to directly express a secretory 35 form of A40 or A42, eliminating the need for amyloidogenic APP proteolysis. Following 36 neuronal differentiation edited cell lines specifically accumulate aggregated/oligomeric A, 37 exhibit a synaptic deficit and have an abnormal accumulation of endolysosomal vesicles. Edited 38 cultures progress to a stage of overt ND. All phenotypes appear at earlier culture times for A42 39 relative to A40. Whole transcriptome RNA-Seq analysis identified 23 up and 70 down 40 regulated genes (DEGs) with similar directional fold change but larger absolute values in the 41 A42 samples suggesting common underlying pathogenic mechanisms. Pathway/annotation 42 analysis suggested that down regulation of extracellular matrix and cilia functions are 43 significantly overrepresented. This cellular model could be useful for uncovering mechanisms 44 directly linking A to neuronal death and as a tool to screen for new therapeutic agents that slow 45 or prevent human ND. Introduction47 Alzheimer's disease (AD) is a chronic progressive neurodegenerative disorder with a decade's 48 long preclinical phase. Clinical features include memory loss accompanied by progressive 49 cognitive dysfunction, cortical atrophy and ultimately death. Neuropathology is well defined by 50 a widespread accumulation of two prominent lesions in cortical brain regions: amyloid plaques 51 and neurofibrillary tangles. Plaques are composed primarily of higher-ordered aggregates of 52 small A peptides derived from amyloidogenic proteolysis of a large transmembrane amyloid 53 precursor protein (APP). Tangles are composed largely of hyperphosphorylated aggregates of a 54 microtubule stabilizing protein tau, a product of the MAPT gene. All forms of AD exhibit 55 accumulation of both A plaques and neurofibrillary tangles and both are considered necessary 56 for a definitive postmortem diagnosis [1]. Both plaque and tangle neuropathology correlate with 57 decrements in cognitive function in AD, but our mechanistic understanding of how these lesions 58 contribute to progressive neurodegeneration (ND) is still incomplete [2]. The reasons for this 59 include the inherent complexity of the disease as well as inadequacies of current animal and 60 cellular experimental models. 61 There are two general forms of AD: a rare autosomal dominant familial form (FAD) and the 62 more prevalent sporadic form (SAD). Both FAD and SAD have a complex genetic component 63 (i.e. >20 identified risk alleles with APOE4 being the most prominent), significant life-style 64 associations (obesity, sleep, exercise, etc.), several associated co-morbidities (i.e. diabetes, head 65 trauma), and of course the most important correlate of all, old age. This complexity coupled with 66 the lengthy time course of the disea...

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Neurodegeneration: From cellular concepts to clinical applications

Abstract: Developing therapies for neurodegenerative diseases will require new scientific approaches that takes into account the complex multicellular interactions of the nervous system.

Cited by 89 publications

References 31 publications

A course-based undergraduate research experience examining neurodegeneration in Drosophila melanogaster teaches students to think, communicate, and perform like scientists

A course-based undergraduate research experience examining neurodegeneration in Drosophila melanogaster teaches students to think, communicate, and perform like scientists

Polygenic Risk Scores in Neurodegenerative Diseases: a Review

A human embryonic stem cell model of Aβ-dependent chronic progressive neurodegeneration

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