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Genetics Overview

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					Genetics Overview
• 30,000 - 40,000 genes • Two copies of each (except X&Y)
– homozygous – heterozygous

• Dominant vs. Recessive
– loss of function – gain of function

“Nature or nurture” problem
To what extent our

genetic background
vs.the

external environment
determine our behavior ?????

Example: phenylketonuria
• • • • 1 in 15,000 children Recessive mutation Phenylalanine hydroxylase makes tyrosine Treatment: reduce phenylalanine in diet

Identical Twin Studies
- Raised Apart - Raised Together

Psychological features dependent on genetic or on environmental factors in three different studies

Knock-in or knock-out transgenic animals are valid tools for neuroscience research

Example of mutations affecting behavior
• • • • • Leptin – Feeding Serotonin – Impulsive behavior Dopamine – Locomotion and motivation Opsin – Color vision Huntingtin – Huntington’s Disease

Huntington disease: As in many other genetic diseases, the mistaken repeat of a triplet (CAG) produces an anomalous protein, of yet unknown function, that is associated with HD symptoms. The longer the repeat, the younger the age of onset of the disease.

There are two opposite ways in which genes are involved in a disease: 1) A defect in a single gene impairs the function of a protein causing the disease (monogenetic origin, like Huntington disease) 2) The concomitance of more than one defective genes causes the appearance of the symptoms (polygenetic origin, like hypertension and diabetes)

• Schizophrenia has a clearly polygenetic component, involving possibly 3-10 genes.
• The co-existance of specific allelic polymorphisms, that per-se are not pathologic might be at the origin of psychotic symptoms characteristic of schizophrenia

Neurons are different from most other types of cells because they possess long processes:
What structures determine the characteristics of neuronal cytoskeleton?

Structural protein of the neuron
• Microtubules • Neurofilaments • Microfilaments

Microtubules
• Form long scaffold of neural processes • 25% of total protein in neurons • Largest diameter 25 nm • Cylinder of 13 protofilaments – polarized • Composed of alternating  and  Tubulin subunits - six genes and 20+ isoforms - grows in size catalyzed by GTPase • The polymer is stabilized by MAPs

Microtubules grow in a helical fashion. Their growth is stopped by “capping” their growing end with GDPbound tubulin. In the absence of MAPs or other stabilizeing proteins they depolymerize, disrupting the structure of the corresponding process

MAP2: dendrites MAP3 and tau prot: axons

Map-2 staining in dendrites not axons

Neurofilaments
• • • • Most abundant fibrillar protein in axons 10nm in diameter Most abundant in axons Related to keratin
– Very stable – Neurofibrillary tangles

Microfilaments
• 3-5 nm in diameter – thinnest of the three elements of cytoskeleton • Made of polarized actin monomers – highly conserved and abundant in living things

• Highly dynamic – half exists as monomers
• Many actin binding proteins secure cytoskeleton to plasma membrane

• Actin is organized in small polymers, and is localized at the periphery of neurons, where it is responsible for shaping processes like growth cones and dendritic spines. • -actin is most abundant in the skeletal muscle • - and -actin are present in neurons

Morphological plasticity
The dynamic state of microtubules and microfilament allow the mature neuron to withdraw or extend old process and form new ones

Microtubule Domains in the axon

Microtubules and actin filaments are the TRACK along which proteins and organelles are moved by molecular motors

Motors
• Actin motors = myosin
– in muscle – actomyosin
– Axons have polarized microtubules, giving rise to orderly movements of proteins from or to the cell body – Dendrites have NO polarized microtubules, giving rise to a more “disordered” morphologica structure, where proteins and organelles can be moved in either direction within the same volume

Spines can be considered as specialized organelles for performing spatially localized dendritic (input) functions

Dendritic Spines