Monogenic vs. Complex Disorders: Isolating the molecular defects of - - PDF document

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Monogenic vs. Complex Disorders: Isolating the molecular defects of Alzheimers Disease Scott A. Small Columbia University Brain Disease Monogenic Complex Fragile X Syndrome Autism Tay-Sachs Schizophrenia Dystonia

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Monogenic vs. Complex Disorders: Isolating the molecular defects of Alzheimer’s Disease

Scott A. Small Columbia University

Brain Disease

Monogenic

Fragile X Syndrome
Tay-Sachs
Dystonia
Hereditary Ataxias
Wilson Disease
Huntington Disease

Complex

Autism
Schizophrenia
Epilepsy
Alzheimer disease
Parkinson disease
ALS

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2 Alzheimer Disease

Monogenic

Early Onset Alzheimer

Disease (EOAD)

Familial
5%

Complex

Late-Onset Alzheimer

Disease (LOAD)

Sporadic
95%

EOAD LOAD

Anatomy

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Small SA, Nature Neuroscience, 2005

Pathophysiology Histology

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4 Histology

Aβ peptide

soluble insoluble

Tau protein

Amyloid Plaques Neurofibrillary Tangles

β-cleavage γ-cleavage BACE APP

Gamma secretase

Aβ TGN Endosome

ER NUC

Lysosome

Aβ Aβ Aβ

Molecular & Cell Biology

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5 Molecular Defects in Monogenic Disorders

1. Law of "Segregation of Characteristics.“
2. Law of "Independent Assortment".

Statistical Models: Pinpointing Genetic Defect Molecular Techniques: Large-Scale Genetic Profiles

Single Nucleotide Polymorphisms (SNPS)

Molecular Defects in Early-Onset AD

APP(ch21q21.3) Presenilin1 (ch14q24.13) Presenilin2 (ch1q31.42)

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6 Molecular Defects in Late-Onset AD

Apolipoprotein E (APOE): ε2, ε3, ε4 (ch19q13.2)

Roberts JS, et al, J Geriatr Psychiatry Neurol, 2005

Genes Gene Products Genes Gene Products Genes Gene Products Genes Gene Products

Liver Cells Region A Region B Brain Cells

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7 Genes Gene Products Genes

Alzheimer’s Disease Healthy

Gene Products Twin A Twin B

Statistical Models: Pinpointing Molecular Defects Molecular Techniques: Large-Scale Genetic Expression Profiles Microarray

Molecular Defects in Complex Disorders

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Pt 1 control Pt 2 Pt 3 Pt 1 control Pt 2 Pt 3 Pt 1 control Pt 2 Pt 3 Pt 1 control Pt 2 Pt 3 Pt 1 control Pt 2 Pt 3 Pt 1 control Pt 2 Pt 3 Pt 1 control Pt 2 Pt 3 Pt 1 control Pt 2 Pt 3 Pt 1 control Pt 2 Pt 3 Pt 1 control Pt 2 Pt 3 Pt 1 control Pt 2 Pt 3

Expression Level

Spatial Information Temporal Information

CA1 SUB

CA3 DG

Spatial Information

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CA1 SUB

CA3 DG

Spatial Information Temporal Information Normal Retromer Function Retromer Dysfunction (VPS35, VPS26 knock-down)

TGN

Endosome

TGN

Endosome

Retromer Trafficking

VPS26 SNX1/ 2 VPS29 VPS35

Annals of Neurology, 2005

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A. Manipulate molecules

Aβ levels

B. Manipulate molecules

Memory loss, synaptic dysfunction, Aβ levels

C. Test for polymorphisms

Risk for developing Alzheimer’s disease

20 40 60 80 100 120 140 160

Non-silencing control

VPS35 siRNA Abeta levels %

20 40 60 80 100 120

Empty vector control

VPS35 transfection Abeta levels %

Annals of Neurology, 2005

2 4 6 8 1 2 3 4 30 minute delay

Trials E rro rs

2 4 6 8 10 12

WT KO

L e v e ls

Aβ40

2 4 6 8 10 12

WT KO

L e v e ls

Aβ40

2 4 6

WT KO

Levels

Aβ42

2 4 6

WT KO

Levels

Aβ42

VPS26 SNX1/2 VPS29 VPS35

1. APP
2. Sorla

(BACE)

3. Sortilin

(BACE)

Cell Culture Mouse Models Human Disease

VPS35 levels

1 1.2 1.4 1.6 1.8

wildtype knockdown

VPS35 levels (normal) 1 1.2 1.4 1.6 1.8

WT KO

VPS35 levels (normal)

VPS35 Retromer-Deficient Hippocampal-Dysfunction Increased endogenous Aβ Memory Retromer Cargo

VPS26 levels

2 4 6 8 10 12

wildtype mutant

VPS26 levels (normal) 2 4 6 8 10 12

WT KO

VPS26 levels (normal)

VPS26 W T WT KO CT siRNA APP/BACE Co-Localization

Risk for Late-Onset Alzheimer’s Disease

Nature Genetics, Under Review VPS26 SNX1/ 2 VPS2 9 VPS35

sorLA sortilin

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Annals of Neurology, 2005

Molecular Defects in Complex Disorders

Statistical Models: Pinpointing Molecular Defects Molecular Techniques: Large-Scale Genetic Expression Profiles

Microarray Functional Imaging

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