Taub Institute: Genomics Core
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TaubCONNECT Research Perspectives:
May 2019

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May 2019:

» #1 Association of Variants in PINX1 and TREM2 With Late-Onset Alzheimer Disease

» #2 Brain Biomarkers and Cognition Across Adulthood

April 2019:

» #1 Predicting Cognitive Improvement in Normal Pressure Hydrocephalus Patients Using Preoperative Neuropsychological Testing and Cerebrospinal Fluid Biomarkers

» #2 Brain Arterial Dilatation and the Risk of Alzheimer's Disease

March 2019:

» #1 Elevated Cellular Cholesterol in Familial Alzheimer's Presenilin 1 Mutation is Associated with Lipid Raft Localization of Ī²-Amyloid Precursor Protein

» #2 FDG-PET Patterns Associated with Underlying Pathology in Corticobasal Syndrome

February 2019:

» #1 Effect of Aerobic Exercise on Cognition in Younger Adults: A Randomized Clinical Trial

» #2 Exercise-linked FNDC5/Irisin Rescues Synaptic Plasticity and Memory Defects in Alzheimerā€™s Models

January 2019:

» #1 A Tau Homeostasis Signature Is Linked with the Cellular and Regional Vulnerability of Excitatory Neurons to Tau Pathology

» #2 Between-network Functional Connectivity Is Modified by Age and Cognitive Task Domain

December 2018:

» #1 Epigenome-Wide Study Uncovers Large-Scale Changes in Histone Acetylation Driven by Tau Pathology in Aging and Alzheimerā€™s Human Brains

» #2 Semantic Network Function Captured by Word Frequency in Nondemented APOE Īµ4 Carriers

November 2018:

» First Place: NSUN2 is Dysregulated in Alzheimer's Disease

» First Place: High-throughput Disease Modeling to Uncover Shared and Unique Characteristics Among Neurodegenerative Diseases

October 2018:

» #1 Homeostatic Plasticity Scales Dendritic Spine Volumes and Changes the Threshold and Specificity of Hebbian Plasticity

» #2 An MRI Measure of Degenerative and Cerebrovascular Pathology in Alzheimer Disease

» #3 Integrative Transcriptome Analyses of the Aging Brain Implicate Altered Splicing in Alzheimer's Disease Susceptibility

September 2018:

» #1 Clinical Experience with Cerebrospinal Fluid AĪ²42, Total and Phosphorylated Tau in the Evaluation of 1,016 Individuals for Suspected Dementia

» #2 Evaluation of TDP-43 Proteinopathy and Hippocampal Sclerosis in Relation to APOE Īµ4 Haplotype Status: A Community-Based Cohort Study

August 2018:

» #1 A Multi-Omic Atlas of the Human Frontal Cortex for Aging and Alzheimer's Disease Research

» #2 An Alzheimer's Linked Loss-of-Function CLN5 Variant Impairs Cathepsin D Maturation Consistent with a Retromer Trafficking Defect

» #3 Letter and Category Fluency Performance Correlates with Distinct Patterns of Cortical Thickness in Older Adults

July 2018:

» #1 Activating Transcription Factor 4 (ATF4) Regulates Neuronal Activity by Controlling GABABR Trafficking

» #2 Whole-exome Sequencing in 20,197 Persons for Rare Variants in Alzheimer's Disease

June 2018:

» #1 Excess Synaptojanin 1 Contributes to Place Cell Dysfunction and Memory Deficits in the Aging Hippocampus in Three Types of Alzheimer's Disease

» #2 Preparation of Tau Oligomers After the Protein Extraction from Bacteria and Brain Cortices

May 2018:

» #1 Whole Genome Sequencing in Caribbean Hispanic Families Associated with Late-Onset Alzheimer's Disease (LOAD)

» #2 Oligomeric AĪ²1-42 Triggers the Generation of a Retrograde Signaling Complex from Sentinel mRNAs in Axons

April 2018:

» #1 Stabilizing the Retromer Complex in a Human Stem Cell Model of Alzheimer's Disease Reduces TAU Phosphorylation Independently of Amyloid Precursor Protein

» #2 Medical Retirement from Sport after Concussions: A Practical Guide for a Difficult Discussion

March 2018:

» #1 Cross Domain Self-Monitoring in Anosognosia for Memory Loss in Alzheimer's Disease

» #2 White Matter Changes in Alzheimer's Disease: A Focus on Myelin and Oligodendrocytes

February 2018:

» #1 ZCCHC17 is a Master Regulator of Synaptic Gene Expression in Alzheimer's Disease

» #2 Imaging Translocator Protein as a Biomarker of Neuroinflammation in Dementia

» #3 A Transcriptomic Atlas of Aged Human Microglia

January 2018:

» #1 Neuronal Lysosomal Dysfunction Releases Exosomes Harboring APP C-terminal Fragments and Unique Lipid Signatures

» #2 An Inflammation-Related Nutrient Pattern is Associated with Both Brain and Cognitive Measures in a Multiethnic Elderly Population

CpGā€Related SNPs in the MS4A Region Have a Doseā€Dependent Effect on Risk of Lateā€“Onset Alzheimer Disease

   Philip L. De Jager, MD, PhD   
Yiyi Ma, MD, PhD   Philip L. De Jager, MD, PhD    Richard Mayeux, MD, MSc

Epigenetic effects such as DNA methylation have been reported in Alzheimerā€™s disease (AD). DNA methylation associated with genetic variation occurs because of the attachment of a methyl group directly to a DNA nucleotide, specifically dinucleotide comprised of cytosine and guanine (CpG). CpG-related single nucleotide polymorphism (CGS) alter the sequence of the primary target sites for DNA methylation and account for a significant fraction (38% to 88%) of allele-specific methylation regions in the human genome. The combined effect of multiple nearby CGSes may play a unique role in AD. For example, the two single nucleotide polymorphisms (SNPs) encoding different APOE isoforms, the strongest genetic risk variants for AD, are CGSes and the number of CpG sites on the two chromatids is genotype dependent. Thus, APOE Īµ2/Īµ2, Īµ3/Īµ3, and Īµ4/Īµ4 homozygotes have 0, 1 and 2 CpG sites, respectively.

Dr. Yiyi Ma, along with Taub faculty members Drs. Philip De Jager, Richard Mayeux, and colleagues, conducted the first and largest region-based, CGS-focused, sliding window approach to measure the combined effects of multiple CGSes on AD risk in a discovery sample of 24 European ancestry cohorts (12,181 cases, 12,601 controls) from the Alzheimer's Disease Genetics Consortium (ADGC) and replication sample of seven European ancestry cohorts (7,554 cases, 27,382 controls) from the International Genomics of Alzheimer's Project (IGAP). The potential functional relevance of significant associations was evaluated by analysis of methylation and expression levels in brain tissue from the Religious Orders Study and the Rush Memory and Aging Project (ROSMAP), and in whole blood from Framingham Heart Study participants (FHS).

Figure. a, Graphical abstract of the study. b, Forest plot of dose-response effect of the number of CpG dinucleotides created by the CGSes in the intergenic window close to MS4A4A on the logged odds ratio of AD. The filled square and horizontal line for each population or the filled diamond for the summary denote the estimated logged odds ratio and its 95% CI per unit increase in the number of CpG dinucleotides in the window.

Results of the study were published in Aging Cell, where the authors identified windows at BIN1, MS4A6A, MS4A4A, PICALM, and APOE. The total number of CGS-derived CpG dinucleotides in the window near MS4A4A was associated with AD risk, brain DNA methylation, and gene expression in brain and blood. Pathway analysis of the genes responsive to changes in the methylation quantitative trait locus signal at MS4A4A (cg14750746) showed an enrichment of methyltransferase functions. Herein, Ma et al. confirm the importance of CGS in AD and the potential for creating a functional CpG dosage-derived genetic score to predict AD risk.

Yiyi Ma, MD, PhD
Postdoctoral Research Scientist
Multiple Sclerosis Clinical Care and Research Center
Center for Translational & Computational Neuroimmunology

Philip L. De Jager, MD, PhD
Weil-Granat Professor of Neurology (in Neurology, the Taub Institute for Research on Alzheimer's Disease and the Aging Brain and the Precision Medicine Initiative)

MFN2 Mutations in Charcotā€“Marieā€“Tooth Disease Alter Mitochondria-Associated ER Membrane Function but Do Not Impair Bioenergetics

Delfina Larrea, PhD    Eric A. Schon, PhD

Charcotā€“Marieā€“Tooth disease type 2A (CMT2A) is a form of peripheral neuropathy, due almost exclusively to dominant mutations in the nuclear gene encoding the mitochondrial protein mitofusin-2 (MFN2). Clinically, patients exhibit progressive sensory loss in the extremities and pes cavus, among other features, with the disease presenting as early- or late-onset forms. Approximately 100 pathogenic mutations in MFN2 have been described, but there is no understanding of the relationship of clinical phenotype to genotype.

MFN2 has two functions: it promotes inter-mitochondrial fusion and mediates endoplasmic reticulum (ER)ā€“mitochondrial tethering at mitochondria-associated ER membranes (MAM). MAM regulates a number of key cellular functions, including lipid and calcium homeostasis, and mitochondrial behavior.

Figure 10: Working model of pathogenesis in CMT2AMFN2. The severity of the disease may be related to the degree of ERā€“mitochondrial communication.

However, the mechanism underlying the pathogenesis of CMT2A has been elusive. One question has been the role of mitochondria in the pathogenic process, rendering confounding results probably by the approach selected such as MFN2 overexpression. This is especially problematic when dealing with a dominantly inherited disorder in which both wild-type (WT) and mutant alleles are expressed, and whose equilibrium may be important in determining pathogenesis. Due to the role of MFN2 in MAM-mediated ERā€“mitochondria interactions, Taub faculty member Dr. Eric Schon, along with first author Delfina Larrea, Marta Pera, Orhan Akman, Estela Area-Gomez, Cristina Guardia-Laguarta, Kevin Velasco and colleagues, asked if MFN2 mutants have altered ER-mitochondria interactions and MAM functions.

As recently published in Human Molecular Genetics, using fibroblasts from three CMT2AMFN2 patients with different mutations in MFN2, Larrea et al. found that some, but not all, examined aspects of ERā€“mitochondrial connectivity and of MAM function were indeed altered, and correlated with disease severity. They also found that the respiratory chain function in those cells was unimpaired.

The results of this work suggest that CMT2AMFN2 is a MAM-related disorder but is not a respiratory chain-deficiency disease. The alterations in MAM function described here could also provide insight into the pathogenesis of other forms of CMT.

Delfina Larrea, PhD
Associate Research Scientist in the Department of Neurology

Eric A. Schon, PhD
Lewis P. Rowland Professor of Neurology (in Genetics and Development)

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