The Importance of Genetics and Omics in Neurodegenerative Diseases

Question 1

Neuropathology of AD

Answer 1

Loss of brain volume, hippocampal atrophy, enlarged lateral ventricles

Abeta extracellular plaques, neurofibrillary tangles, cerebral amyloid angiopathy

Question 2

Neuropathology of PD

Answer 2

Loss of dopaminergic neurons in substantia nigra

aSyn lewy body and lewy neurites

Question 3

Neuropathology of FTLD

Answer 3

Heterogenous depending on which protein is accumulating - TDP-43, tau, FUS

Different genes implicated in different subtypes

FTLD-TDP makes up 50% of all FTLD cases

Question 4

Genetics: Loci Discovery

Answer 4

Helps to detect genetic variants associated with neurodegenerative diseases

Variants can be Mendelian (disease-causing, high penetrance) or risk alleles (low penetrance, small risk can be cumulative/interact with environment)

Question 5

AD Genetics

Answer 5

Mendelian genes: APP, PSEN1, PSEN2

APOE4 is the strongest risk factor for late-onset AD

Question 6

PD Genetics

Answer 6

Autosomal dominant and recessive genetic loci associated with familial PD

PARK1/4 - AD, PARK2 - AR

SNCA encodes for aSyn -> variants associate with familial form and risk of sporadic form

Question 7

AD Ataxia Genetics

Answer 7

Repeat expansions are most common form of mutation

Inherited mutations

ATXN3, ATXN1/2/7, CACNA1A

Question 8

Benefits of Genetics in Neurodegenerative Diseases

Answer 8

1. Allows genetic testing and diagnosis of Mendelian forms of disease
2. Improved genetic counselling
3. Use for predictive and/or prenatal testing
4. Allows predictions of disease risk/onset/prognosis

Question 9

Clues from Mendelian Diseases

Answer 9

Overproduction of certain deposited proteins leads to earlier onset of disease -> shows us that it is harmful to have too much of a certain gene

Question 10

Use of Identifying Genes

Answer 10

Once risk genes are identified, we can find out what the genes do, what different risk genes have in common

This can help us to determine if there are pathways which can be targeted instead of individual genes
-> can use pathways to help modify phenotype or prevent disease

Can help us to determine why different gene mutations can cause the same type of disease

Question 11

Treatment Strategies

Answer 11

1. Prevent gene being transcribed in nucleus
2. Target mRNA for degradation
3. Target faulty protein
4. Target clearance of protein

Question 12

Epigenomics

Answer 12

One DNA sequence can produce multiple phenotypes

Epigenetics converts a static DNA sequence to dynamic gene expression

Most common epigenetic modifications are:
- Histone methylation
- Histone acetylation
- Histone phosphorylation
- Histone ubiquitination
- DNA 5-methylcytosine addition
- DNA 5-hydroxymethylcytosine additions

Question 13

Module Trait Relationships

Answer 13

Create weighted gene co-methylation networks

Looks at groups of genes associated with disease rather than individual changes

Identify what they have in common and what pathways are affected

Can identify genetic and epigenetic overlap -> different mechanisms may be leading to changes in the same gene

Question 14

Transcriptomics

Answer 14

Looks at mRNA

Can compare gene by gene or by more systems approaches

Use normal brain transcriptomic to find out what genes are doing to identify how the mutations may cause disease

Can identify particular pathways present in certain networks in different areas of the brain

Can also compare different diseases with shared risk genes to see if they have anything in common and what cells are associated with those genes

Question 15

Polygenic Risk Scores

Answer 15

Used to stratify patients for clinical trials

Overall risk score is made up of many variants with different effect sizes

Only some genetic variants may benefit from a particular drug

Question 16

Gene-Manipulation Tools

Answer 16

Used to target DNA sequences or gene expression

Genome editing by engineered nucleases or ASOs

Essential to know where mutations are for their design

Question 17

Gene-based therapy

Answer 17

One dose for life, but difficulty in delivering therapy to correct cells

Question 18

Epigenetic-based therapy

Answer 18

Modify histone modifications or DNA methylations at a particular position
-> need to ensure safety and delivery to the correct cells/part of brain