Transcript Introduction to biol..

Introduction to neurobiology
Teacher: Neta Zach
([email protected], 03-5610921,052-2574626)
Course site (my alice account)- alice.nc.huji.ac.il/~netazach
(includes tutorials, assignments and the articles mentioned in class/tutorial)
Course requirements and grade:
• 8 exercises, which should be submitted on the following week
either via e-mail (deadline Monday 23:59) or printed. 5% of final
grade
• 3 assignments (reading an article and answering questions
about it). 15% each
• Final (home test) assignment –reading of a second article. 50%
Introduction to cellular function IGenetics
Why study physiology?
All are capable of:
•Metabolism
•Reproduction
•Growth
•Respiration
Animal’s specialty- being able:
•To Move
•To respond to stimuli
Meaning:
Functionally,
Central nervous system
= animal
Mechanically, however,
animal is a group of cells
1. Like unicellular organisms, animal cells can look after
themselves.
2. The shift from eukaryota to animalia is in union and
specialization- they also care for one another.
• Before we ignore statement #1 completely, two lessons
need to pass…
What a cell needs for us to ignore it
• Osmotic balance
• Electrical balance
• Ionic concentration balance
This is how we will usually
treat a cell- a black box with
input and output
What a cell actually needs
•
•
•
•
•
Maintenance
Reproduction
Metabolism
Growth
Garbage disposal
And the functions that would make a body (the black box
from the outside)
Cell- a general scheme
Memebrane,
Nucleulos (in nucleus)
cytosol
Lysosome (disposal) (maintenance, reproduction)
Endoplasmatic
reticulum
(transport),
Dotted by
ribosome
(maintenance)
Mitochondria
(respiration,
nutrition)
Cellular information's elementary
unit is DNA
Griffith 1922
• S stain is lethal
• R stain isn’t
• Dead S stain isn’t lethal
• Dead S stain+R stain is
=> Lethality trait is in the DNA
Cellular information's
elementary unit is DNA
All the information necessary to replicate all cells of a particular
organism is coded in its genes (meaning- later).
Genes are chains of nucleic acids(DNA), which include
phosphate + sugar (pentose, 5 carbon structure) + base.
bases can be one of 4:
adenine (A)
Hydrogen bond
guanine (G)
cytosine (C)
thymine (T)
The double helix model (watson &
crick)
• a sugar+phosphate+sugar+
phosphate chain holds bases
(attached to sugar) together
• Bases face each other to form
hydrogen bonds A=T, G=C to
create a coil made of intervening
helixes .
Gene packaging
DNA is wrapped around regulatory proteins
called histones to form nucleosome
Nucleosomes are arranged in
helix
a sphere- coiled coil.
A group of nucleosomes
histones
is called a Chromatin.
The entire length of the chromatin =
chromosomes
nucleosome
Chromatin I
chromatin
Chromatin II
Coiled coil
chromosome
nucleosome
Why do we call it genetic
information
The genius of Watson and Crick:
the double helix structure allows replication, i.e
heredity. But it will be proven informative
only if can direct protein synthesis:
Unlike glucose or fatty acids,
the variety of amino acids types
(20 n combinations of different side chains)
allows… well, every known bodily function
amine
group
unique
side chain
a proton
a - Carbon
Protein synthesis-transcription
• RNA polymerase I/II/III attaches to DNA=>double helix opens
• RNA bases (AUGC) match the helix, forming a complementary
RNA helix.
• RNA helix’s unnecessary parts
(introns) are removed by splicing out,
leaving only exons
=> messenger RNA(mRNA)
Protein synthesistranslation
mRNA leaves the nucleus through pores to:
1. Endoplasmatic reticulum (ER) or 2. cytosol
Either way to ribosome:
•
3 RNA molecule form a codon.
•
Starting codon- AUG
•
tRNA attaches specifically to codon,
carring an amino acid.
•
Peptidyl transferase
connects amino acids
•
Ribosome jumps a codon
•
Termination-stop codon
Structure of proteins
From ribosome- primary structure
Naturally fold to secondary structure.
a-helix and b-sheets are common motifs.
Structure of proteins II
• Tertiary structure is
full 3D folding, sometime
requires assistive
proteins- chaperons,
occurs at Golgy
apparatus or cytosol
• Quaternary structure is
formed by several
polypeptide subunits
tertiary structure
quaternary structure
Protein structure summary
ER
From ribosome,
(ER/cytosol), natural folding
Advanced folding and modification,
(Golgy apparatus)
Golgy
Protein synthesis - summary
Splicing out
folding
Functions of proteins- enzymes
chemical reactions (intro)
Laws of thermodynamics:
1. The total energy of a system and its surroundings is constant
2. The total entropy of a system and its surroundings always
increases in a spontaneous process
=>If a reaction seems to reduce entropy, then energy is released
as heat (increasing surrounding disorder).
Measurement: Gibbs free energy: spontaneous reaction G  0
G  0
equilibrium state
requires energy input G  0
Functions of proteins- enzymes
(how)
Binds specific substrates and
accelerates specific reactions
through conformational change,
(Sometimes using coenzymes)
E + S
Lock-and-key
Induced fit
ES
EP
E + P
Specificity is due to enzyme’s
elaborated 3D structure
Functions of proteins- enzymes
(what)
Reaction types:
1. Isomerization, A->B - structural rearrangement without
any change in its net atomic composition
2. Synthesis, A+B->C - combination of two or more
elements (RNA polymerase, for example)
3. Analysis( Decomposition), A->B+C – decomposition to
smaller compounds
4. Substitution (single displacement), A+BC->AC+B –
shifting of one element between compounds.
5. Substitution (double displacement), AC+BD-> AB+CD
exchange of single elements between compounds.
Functions of proteins- beyond
enzymes
• The one gene one enzyme idea (Beadle & Tatum) :
Advantages: Solved a lot of diseases (genetic therapy).
Disadvantages: unrealistic.
Rhys evans was a
bobble boy (had
SIDS). Now he’s not
• Two mistakes:
1. Not one gene-polygenetic trait (from personality to cancer …
all that is not clearly hereditary)
2. Not an enzyme- most of what the body needs is not reactions,
it’s regulation-signaling, markering, protein networks…
Reproduction (cellular)- Mitosis
Stage I- replication:
•Helicase breaks helix,
•Primase transcribes matching RNA
•DNA Polimerase transcribes back to DNA- Okazaki fragments.
•Occurs simultaneously at multiple sites, unidirectional
At the end:
• DNA ligase attaches fragments
• Holoanzyme attaches the
identical (not complementary!)
helixes- sister chromatids
Stage II-Mitosis
Nuclear envelope breaks, chromosomes align in cytosol
Microtubules (cytoskeleton),
attach to centromer, align at
two poles and start shortening,
thereby pulling chromosomes
until rapture.
Prophase
Prometaphase
Metaphase
Anaphase
Cell pinches inward to
create two cells
Telophase
Reproduction (cellular) –when
Formally, mitosis is part of the cell cycle, thus the
tissue lives forever. However, animal cells
acquire their very specific functions through
differentiation and cell cycle ceases (why?).
(exceptions- the liver)
Solution- a stock of undifferentiated stem cells.
Requires:
• control of the fate of a tissue
• ability to guide differentiation by external signals
alone.
Green
marks
neuronal
stem cells
Neuro-genesis in the human brain
arrows mark new neurons
• Erikson 1998- new cells in
the Hippocampus. 2000also olfactory bulb. Cortexunclear.
• What does it mean?
Green marks new cells
Brain transplant?
(someone else's
stem cells)
Sexual reproduction- meiosis
One diploid cell divides to 4 haploid cells(gametas):
• Replication-like mitosis(46 pairs of sister cromatids)
• Division I - 23 pairs on each daughter cell.
• Division II-pair separation (like mitosis)
=> 4 cells, half the
information
Where genetic variability kicks inMutations
Source: Structural change in the replicated DNA strand (radiation,
oxidative damage...mutagen) or replication error.
Types: 1)Attaching the wrong base or deletion/insertion of one
base- point mutation. Can be neutral, silent, missense or
nonsense.
2)Changes of many bases: deletion/insertion or Defects in
Okazaki fragment attachment- translocation, deletion, inversion
(fragile X, Down syndrome…)
Where genetic variability kicks ineffects of mutations
Point mutation can eliminate /create /increase /decrease /reverse
a certain function.
Occurs in transcription>mitosis>meiosis (better control)
Importance: Recombination, chromosomal translocation
occurring in meiosis between mother’s chromatid and father’s
cromatid (“crossing over”)- breaking the linkage between
genes to create new combinations of traits.
•From recombination frequency, distance
between genes can be calculated
•Poorly understood- unity of traits, silent X…
Examples of induced “natural”
selection
20 generations
Agent orange, atomic bomb…
Expression
For all but X and Y we have 2
homologies chromosomes=>two
alleles. Same is called
Homozygote, differentHeterozygote.
Heterozygote-We are interested in
what will the trait be Phenotype vs.
Genotype) :
One gene is dominant over the otherDominant expresses-examplesnormal enzyme vs defected,
pigment vs. albino.
(mechanism- one gene is quite
enough or stronger (pigment) or
mechanically favorable
Both are evidenced in phenotype-”blend”/mixed (Incomplete
dominance)Mechanisms-1.both expressed (examples-carnation, snapdragon
and roses, when pink, are “daughters” of red and white parents.
2. Only one expressed in each cell completely
randomly (examples-grey pets have black and white hair cells).
Mechanism-mechanically favoring one allele.
3. If expression is in patches- selection of one allele
but done early in development.
Note: not always one allele is favorable!
Genetic expression
mixed patches
dominant- always expressed
in trait
recessive-expressed if
second copy is same
mixed-dots
Introduction to cellular function IIcellular processes
What a cell actually needs
•
•
•
•
•
Maintenance
Reproduction
Metabolism
Growth
Garbage disposal
And the functions that would make a body (the black box
from the outside)
Cell- a general scheme
Memebrane,
Nucleulos (in nucleus)
cytosol
Lysosome (disposal) (maintenance, reproduction)
Endoplasmatic
reticulum
(transport),
Dotted by
ribosome
(maintenance)
Mitochondria
(respiration,
nutrition)
Nutrition-general
Requirements: substrates, energy.
Substrate, how: polymers (food) ->monomer->polymer
Catabolism- break down, energy released.
Anabolism-building up, energy required,
• Substrate, what: Protein (amino acids)-mostly muscles, energy
Fat (fatty acids)-membranes, energy
Carbohydrate (glucose)-energy only.
Few-minerals and vitamins for co-enzymes
Nutrition-energy
ATP
• Cell receives glucose and through glycolysis (in cytosol)
produces pyrovate + ATP
Glycolysis
If oxygen isn’t present- free protons
are moved to lactate and out as
disposal (fermentation) -anaerobic
respiration
The tie between nutrition and
respiration- mitochondria
Organelle of endosomic origin and maternal
heredity, double membrane with invaginations
that form a membranal matrix.
If oxygen is available, Pyrovate is transferred to
(using Porins(co-anzyme A =>Krebs cycle
Products 3 NADH+, FADH+2.
Electron transfer chain:
Passes proton(+) and uses
Energy for ADP+P=ATP(4 times)
Acetyl-CoA + 3 NAD + +FAD + GDP + Pi 2 + H2O →
CoA-SH + 3 NADH + H + +FADH + 2GTP + 2 CO 2 +
3H +
FADH and NADH are electron carriers
Respiration is good for you
• Improvement from(2 ATP):
Glucose
2 ATP, 2 lactate (useless)
To(30 ATP)
Glucose +6O2
ATP production and
breakdown is the
common currency of
cellular energy
6CO2+6H2O+~30ATP
Cleaning up after the meal-lysosomes
Organelles containing enzymes to digest
macromolecules (lipase, Carbohydrase,
protease, nuclease… ).
Purpose: Garbage, bacteria, necrosis
Mechanism-hydrolysis. PH 4.8 (cytosol 7)- Leakage
less harmful (proton pump in (single) membrane)
Importance: Tay-Sachs causes blindness,
deafness, paralysis and death (due to ganglioside GMS
accumulation)
Cleaning up after the mealperoxisomes
Oxidative stress (free radicals) is the main cause of
mutation and cell death (in apoptosis):
To eliminate oxidative stress-(single-membrane) organelles:
2H2O2 (catalase)→ 2H2O + O2.
• No peroxisomes- Zellweger syndrome (mental retardation and
death). But also in cytosol-no superoxide mismutase-ALS
Anyway, oxidative stress still accumulates:” Apples brown.
Butter turns rancid. Iron rusts. brain degenerates.”
• Solutions?
ER
Transportprotein transport
The way of the protein: Nucleus-rER-(golgi),
transport from rER to golgi- vesicles (createdwith other lipids- in sER).
In golgi(cis-> lumen-> trans ): protein
modification- folding, attaching glucose,
phosphate…and out in new vesicles
Golgi
Secretion in vesicles:
Golgi
ER
folds=cisternea
trans
Golgi
out
vesicule
cis
Transport-cellular transportcytoskeleton
3 types:
1.Microtubuli 23-25nm across neuron structure. Circle of 13
subunits (unequal length), each made of a pair of a+b tubulin.
binds GTP->GDP->instability, breakdown-a cycle
->microtubuli constantly
changes length
+
-
Transport-cellular transportcytoskeleton II
2.neurofilaments-10nm most common. cytokratins
alzhaimer-neurofilmentary tangles
(senile plaques). stable
Looks like a neuron
but in fact it’s neurofilaments
3.Microfilaments- 3-5 nm made of actin. Cell
periphery/membrane, for secretion (and muscle
contraction). Changes dynamically.
Cell boundariesmembranes (briefly)
Membranes are lipid bilayers(phospholipids form close
shapes naturally in aqueous solutions), hydrophobic
and therefore impermeable to all polar substances.
Membranes are crossed by proteins, some act as
transporters of polar or large substances: channels
(open/close), pores (“holes”), active pumps (ATP),
transporters (gradient dependent).
Other proteins do not transport materials but transmit their
presence-receptors
To be continued…
Cell boundaries-neuron shape
• Cell body-soma
• Dendrite (generally many)
• Axon
Cell boundaries- shape divergences
• The most diverse human tissue
Cell boundaries - Glia
• Non - neuronal cells, 50:1 more prevalent in the
brain than neurons. Do not possess neurons’ electrical
signaling ability but do respond to/secrete neurotransmitters.
• Believed to provide: structural support, nutrition but mostly
electrical isolation by wrapping neurons with myelin.
• Myelin-fatty acid coating that improves electrical conductance
Glia in CNS- oligodendrocytes
• Myelin coating, only in higher vertebrates each
“Arm” wraps about 1mm of axons
Glia in CNS-astrocytes
• The most common glial cell, surround neurons
and blood vessels and form scar tissue
• Can control neurotransmitter levels
• ”a second neural network" -slower, electrically
coupled and communicates through calcium
waves.
Microglia-similar to
macrophagues, for immunity in
the CNS, and mostly clearing
dying cells from a site of injury
Glia in PNS-schwann cells
• Wrap myelin by spiraling around the axon, sometimes
with as many as 100 revolutions. A well-developed
Schwann cell is shaped like a rolled-up sheet of paper of
1mm diameter.
Quantum theory of mind
First assumption- the mind is a quantum object. Therefore, it
should be comprised of quantal mechanisms
Rational: In Quantum Mechanics a particle can take up several
states at once and then “collapse“ to one state.
The mind has normally several states at once (subconsciously)
and collapses to one-This is the threshold of consciousness.
Evidence : none. Not for the mind description, nor for the
mechanisms.
Problems: numerous. One of them: If metaphors were always to
be followed, we wouldn’t need the word “like” in our
dictionaries.
(”minimization of mystery-both are mystery, therefore related”-David Chalmers)
Second assumption: microtubuli are a good candidate to be
the quantal elements
Rational- 1.unlike neurons, they are small enough.
2. They are constantly being constructed and deconstructed (the
stability point is the consciousness)
3. They, like consciousness, are effected by anesthetics.
Evidence: the above is all correct. The rest is un-researchable.
Problems: 1.in 37 degrees, quantal process should take 10-20
sec. Neuron changes in milliseconds.
2. microtubulis of different cells aren’t connected.
3. Many microtubuli problems are known, none are related to
consciousness.
4. All microtubule effects are well described by regular
mechanics,.
5. Many other things are related to anesthetics.
6. If they had any evidence, maybe we could argue about it,
but they have NONE.