Summary Neurogenomics
Inhoudsopgave
Lecture 1, Mathijs Verhage – Introduc7on ....................................................................................................... 2
Lecture 2, Max Koppers – RNA biology of the neuron ...................................................................................... 6
Lecture 3, Rik van der Kant – Disease modelling and drug discovery for Alzheimer’s disease using IPSCs ....... 17
Lecture 4, Ronald van Kesteren – Interneurons in Alzheimer’s Disease .......................................................... 29
Lecture 5, Vivi Heine – Human-based models: Brain co-cultures & organoids ................................................ 40
Lecture 6, Mathijs Verhage – Polarity and Trafficking ................................................................................... 52
Lecture 7, Michel van den Oever – Iden7fica7on and characteriza7on of persistent memory engrams .......... 61
Lecture 8, Sabine Spijker – Extracellular matrix in depression........................................................................ 74
Lecture 9, Priyanka Rao – Hippocampal synap7c plas7city underlying the modula7on of fear memory ......... 88
Lecture 10, Ruud Toonen – Vesicle Dynamics and Synap7c Plas7city ........................................................... 102
Lecture 11, Mark Verheijen – Glial regulated Neuronal Plas7city ................................................................. 113
Lecture 12, Wiep Scheper – Tau and neurodegenera7on: Mechanisms and therapeu7c targets................... 128
Lecture 13, Guus Smit ................................................................................................................................. 143
Dissec&ng the role of auxiliary subunits in the regula&on of AMPA-type glutamate receptors ..................... 143
Cellular Diversity in the Brain ......................................................................................................................... 156
Lecture 14, Maahijs Verhage....................................................................................................................... 169
Synap&c Plas&city, Synaptotagmin (pre-synapse, short-term mechanism) .................................................... 169
Synap&c Plas&city, CaMKII (post-synapse, long-term mechanism) ................................................................. 179
,Lecture 1, Mathijs Verhage – Introduc7on
Many organisms share genes with humans.
State of art today: Not all informa8on is guiding to the same answer as in text books. Only
when the evidence is sold it will be in text books.
Therapy development is too expensive to do academically; you need to do this most oBen in
a company. But recently, it was shown that it is doable in academia!
Two different approaches to study the brain:
- Derive informa8on from scans like MRI, or brain ac8vity like EEG or ques8onnaires
o Looking from the outside of the brain
o E.g., If you have a new medica8on you can compare it to exis8ng medica8on
- Or you can look at causality, really taking things apart & put them back together
o A mechanis8c approach to neuroscience
o Think about model organisms and cell cultures
If you want to understand the system level, you need to understand the underlying levels.
Es8mated heritability
•Au8sm: 60-80%
•ADHD: 50-70%
•Schizophrenia: 50-60%
•Depression: 30-60%
But it is difficult to understand this heritability.
- Important to understand how we can use this informa8on of gene8cs that iden8fied
the genes. How this contributes to the disease
,Loci: places in the genome
- Single gene (mendelian disease) à to something very complex (polygenic disorder)
- >200 loci involved in schizophrenia, which explains only 10% of the heritability and
your vulnerability to this disease.
Physiological and pathological traits help us understand how a gene is involved in a disease?
Systems biology approach
A lot of approxima8on is involved between different levels
- Only from molecules to organelles can real assump8ons be made up to now
Func8onal genomics
- Each of the genes can be a therapy target, both downstream and upstream of the
muta8on causing the disease
, STBX1
- Taking skin biopsies and from these making IPSCs
- Because there is a single muta8on with a large effect causing clinical symptoms this is
the recept to understand the disease
à pathway to understand the disorder
- Blueprint for more dominant disorders in our society
- By doing this in a systema8c manner you can start to predict complex behaviour of
the human brain
Example: Receptor binds a ligand leading to the ac8va8on of a kinase causing changes in
transcrip8on
- This is a cellular response: how the cell responds to the ligand
- This has been studied in a quan8ta8ve manner
o If you double the amount of ligand, what will then happen to all intermediate
steps
o And most importantly, what happens to the final component
o You could put it in the computer and predict what happens in the end
o Important to understand how variability in gene muta8ons affects the disease
Inhoudsopgave
Lecture 1, Mathijs Verhage – Introduc7on ....................................................................................................... 2
Lecture 2, Max Koppers – RNA biology of the neuron ...................................................................................... 6
Lecture 3, Rik van der Kant – Disease modelling and drug discovery for Alzheimer’s disease using IPSCs ....... 17
Lecture 4, Ronald van Kesteren – Interneurons in Alzheimer’s Disease .......................................................... 29
Lecture 5, Vivi Heine – Human-based models: Brain co-cultures & organoids ................................................ 40
Lecture 6, Mathijs Verhage – Polarity and Trafficking ................................................................................... 52
Lecture 7, Michel van den Oever – Iden7fica7on and characteriza7on of persistent memory engrams .......... 61
Lecture 8, Sabine Spijker – Extracellular matrix in depression........................................................................ 74
Lecture 9, Priyanka Rao – Hippocampal synap7c plas7city underlying the modula7on of fear memory ......... 88
Lecture 10, Ruud Toonen – Vesicle Dynamics and Synap7c Plas7city ........................................................... 102
Lecture 11, Mark Verheijen – Glial regulated Neuronal Plas7city ................................................................. 113
Lecture 12, Wiep Scheper – Tau and neurodegenera7on: Mechanisms and therapeu7c targets................... 128
Lecture 13, Guus Smit ................................................................................................................................. 143
Dissec&ng the role of auxiliary subunits in the regula&on of AMPA-type glutamate receptors ..................... 143
Cellular Diversity in the Brain ......................................................................................................................... 156
Lecture 14, Maahijs Verhage....................................................................................................................... 169
Synap&c Plas&city, Synaptotagmin (pre-synapse, short-term mechanism) .................................................... 169
Synap&c Plas&city, CaMKII (post-synapse, long-term mechanism) ................................................................. 179
,Lecture 1, Mathijs Verhage – Introduc7on
Many organisms share genes with humans.
State of art today: Not all informa8on is guiding to the same answer as in text books. Only
when the evidence is sold it will be in text books.
Therapy development is too expensive to do academically; you need to do this most oBen in
a company. But recently, it was shown that it is doable in academia!
Two different approaches to study the brain:
- Derive informa8on from scans like MRI, or brain ac8vity like EEG or ques8onnaires
o Looking from the outside of the brain
o E.g., If you have a new medica8on you can compare it to exis8ng medica8on
- Or you can look at causality, really taking things apart & put them back together
o A mechanis8c approach to neuroscience
o Think about model organisms and cell cultures
If you want to understand the system level, you need to understand the underlying levels.
Es8mated heritability
•Au8sm: 60-80%
•ADHD: 50-70%
•Schizophrenia: 50-60%
•Depression: 30-60%
But it is difficult to understand this heritability.
- Important to understand how we can use this informa8on of gene8cs that iden8fied
the genes. How this contributes to the disease
,Loci: places in the genome
- Single gene (mendelian disease) à to something very complex (polygenic disorder)
- >200 loci involved in schizophrenia, which explains only 10% of the heritability and
your vulnerability to this disease.
Physiological and pathological traits help us understand how a gene is involved in a disease?
Systems biology approach
A lot of approxima8on is involved between different levels
- Only from molecules to organelles can real assump8ons be made up to now
Func8onal genomics
- Each of the genes can be a therapy target, both downstream and upstream of the
muta8on causing the disease
, STBX1
- Taking skin biopsies and from these making IPSCs
- Because there is a single muta8on with a large effect causing clinical symptoms this is
the recept to understand the disease
à pathway to understand the disorder
- Blueprint for more dominant disorders in our society
- By doing this in a systema8c manner you can start to predict complex behaviour of
the human brain
Example: Receptor binds a ligand leading to the ac8va8on of a kinase causing changes in
transcrip8on
- This is a cellular response: how the cell responds to the ligand
- This has been studied in a quan8ta8ve manner
o If you double the amount of ligand, what will then happen to all intermediate
steps
o And most importantly, what happens to the final component
o You could put it in the computer and predict what happens in the end
o Important to understand how variability in gene muta8ons affects the disease
