Neurobiology: Genetics, Immune System, and Neurological Pathologies - Test 4

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final exam May 2, 2013
updated 9 years ago by lifesurfeit
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1

Genetics

Mechanisms by which changes in the DNA sequence (change, gain or loss) of DNA cause disorder or disease (mutation, polymorphisms, deletions, expansions/copy number gains)

2

Epigenetics

Mechanisms by which chromatin modifying enzymes and accessory proteins modify the structure and function of chromatin (DNA plus associated nucleosomes) This does not involve loss or gain of genetic material, nor any change in base sequence in DNA.
Changes in expression (promoter sequence polymorphism can give rise to changes in methylation status (DNMTs)) and regulation (epigenetic modulation of chromatin structure can be altered by minor changes in the modulators)

3

Types of DNMTs (DNA methyltransferases)

DNMT1- maintenance DNMT, replication; specific to hemi-methylated cytosines
DNMT2- Methylates tRNA-ASP
DNMT3a- de novo methyltransferase; works with 3l in methylating transposons and repeats
DNMT3b- de novo methyltransferase; essential regulator of where and when genome is actively expressed
DNMT3L- de novo methyltransferase; works with 3a

4

Mechanism of DNA methylation

Clip and flip mechanism: DNMT1 (3a,3b) enzymatically and temporarily clips one side of the double helix in order to rotate the cytosine out into the catalytic domain to methylate the 5 position carbon.
S-Adenosyl methionine donates methyl group, added to cytosine
Alters expression of genes

5

HKMTs (Histone Lysine Methyltransferases)

-silencing modifications H3K9, H3K27 trimethylation
-SET domain containing proteins

6

KDMs (Lysine demethylases)

-Jumonji domains
-remove methyl groups for Hist. Tail lysines, alter gene silencing modifications

7

HATs (Histone Acetyktransferases)

Catalyze transfer of Acetyl from acetylCoenzyme A to Histone lysines
Open the structure of DNA

8

HDACs (Histone Deacetylases)

Remove acetyl gourps allowing methylation and silencing by KMTs (PRC1/2)
-Sirt1 in Alzheimer’s

9

PRMTs (Arginine methyltransferases)

Dimethylate arginine residues in histones

10

Transcription/accessory factors

- Necessary for localizing enzyme complexes
BAFs, recruit modifier factors

11

Histones

know the general nucleosome structure and function of the histone N-terminal tails H2a/H2B pairing and H3/H4 pairing in the nucleosome, H1 links the nucleosomal subunits aids in condensation of chromatin into higher order stuctures.

12

Complement molecules

(part of innate immune response)
Initial binding to pathogen activates C3
C3 Signals to body to recruit inflammatory cells, coats microbes and initiates adaptive immune responses.
-Gradual assembly of complement leads to C8/C9 pore formation in microbe’s cell membrane causing lysis (e.g., bacterium

13

Innate immune response

Complement mediated response
Pattern recognition receptors on macrophages

14

Of the two branches of the immune system, the innate and the adaptive branches, the adaptive immune system plays the greatest role in the normal, non-pathological brain.

Due to the restriction of access by the Blood Brain Barrier (BBB) to most circulating leukocytes such as neutrophils, basophils and eosinophils.

15

Macrophages

Primary phagocytes in tissues, present antigens to activate other cells (T, B cells)

16

Monocytes

Circulating in blood, mature into macrophages

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Eosinophils & Basophils

Toxic secretions and respiratory bursts

18

Neutrophils

First responders at a site of infection/damage, attack foreign cells
Most numerous

19

T cells

Function in recognition and killing of foreign cells
T1: cytotoxic, recognize and attack
T2: helper, present antigens

20

B cells

Function in antigen production

21

Toll receptors

Signal a response to a foreign invader, used by macrophages
Binding to a pathogenic stimulant molecule on macrophages signals transcription and release of Interferon and inflammatory cytokines, cause recruitment of immune cells

22

Phagocytosis

Engulfment of foreign material by phagocytes, facilitated by the actin-myosin contractile system

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Inflammatory cytokines

Small signaling molecules that bind to antibodies to produce an immune response

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Dendritic cells

Function in presentation of antigens

25

Antigen presenting cell

Macrophages, B cells, dendritic cells
Processes and presents foreign antigens to activate the immune response via MHC II.

26

Breakdown of the blood brain barrier or toxic responses to chronic pathogens can lead to:

neuronal toxicity (injury, stroke, infection)
neurodegeneration
autoimmunity (MS, VKL).

27

Antigen presentation

Amplifies recognition of pathogens and response
Provides memory of foreign antigens

28

Astrocytes

End-foot maintenance of the BBB, NT reuptake, pH buffering, ionic balance(Na+, Ca++), Apolipoprotein E, protease inhibitors, lysozymes

29

Nervous immune response

Resident migratory macrophages detect local infection.

Leukocytes flow along the vasculature, interacting with surface receptors on endothelial cells.

Esgl1 on the surface of leukocytes interacts with P-Selectin molecules on the surface of endothelial cells.

Chemokine signals emanate from sites of inflammation, causing activation and adhesion of leukocytes

Trans-endothelial migration allows extravasation of leukocytes in the vicinity of inflammation

30

Natural killer cells

Function in lysing foreign cells
Recognizing MHC I or eliminating cells that do not express MHC I (foreign cells, virally infected cells that don't regulate MHC I).

31

Adaptive immune response

Mounted response to recognized particles (antigens) of a foreign entity.
Provides the body with a “memory” of a foreign pathogen or entity
Provides the body with a vaccine mechanism
Longer development period (weeks), but sustained
Antigen recognition by T cells, eliminate pathogens by responding to antigen presenting cells (APCs) such as astrocytes, neurons, and microglia.
Production of antibodies by B cells

32

Small mutations and SNPs

Single nucleotide polymorphism causes frameshift mutations
Found in Tourette's and OCD

33

Tourette symptoms

Vocal/phonic and motor tics, simple or complex
Diagnosed in children 3-8 years, worsen by age 10, crescendo in adolescence, lessens in adults

34

Tourettes syndrome (TS) cause

Loss of one cytosine base (single nucleotide polymorphism, SNP, causing frameshift mutation in SLITRK1
Defects in expression occur in a SLITRK1 promoter mutation
Cause defects in axon/dendrite outgrowth during development

35

Obsessive-Compulsive Disorder (OCD)

coding region mutation in SERT causing aberrant connectivity

36

Both affect development of proper wiring, neurite branching and overall disordered function of neurons.

SERT and SLITRK1

37

Trisomy 21 (Down's Syndrome)

Whole chromosonal translocation

38

Huntington’s Disease (HD)

CAG repeats, autosomal dominant inheritance patterns

39

Fragile X syndrome: spino-bulbar muscular atrophy and E

CGG/CCG repeats, Class III. X linked variety
Repeats outside of protein coding region

40

Trinucleotide repeat diseases

Interrupt protein coding in encoding gene, or transcript.
Midlife onset, progressive dysfunction. Worsening over generations as repeats increase.

41

Both are trinucleotide repeat diseases

Huntington's Disease and Fragile X syndrome

42

Cerebellar ataxia (skip)

Unintentional tremor, gait and balance deficits, progressive
Caused by genetic syndromes, atrophy, multiple schlerosis, alcoholism, vitamin deficiency, peripheral neuropathy (diabetes)

43

Alzheimer's symptoms

Dementia, failure of memory, confusion, poor judgment, language disturbance, agitation, withdrawal, and hallucinations.
Occasionally, seizures, Parkinsonian features, increased muscle tone, myoclonus, incontinence, and mutism occur

44

Alzheimer's causes

Alteration in SIRT1 (HDAC)
Degeneration of ACh neurons in the frontal lobe (nucleus basalis)

45

Tau theory of AD

Tau - microtubule stabilizing protein
Hyperphosphorylation effect on microtubule stability, transport, neurotransmission creating toxic Tau (aggregated, accumulated) tangles.

46

Simplex vs. early onset Alzheimer's

10-15% chance of dementia, increased to 20-25% for first degree family members
vs.
autosomal dominant inheritance

47

Presenilin theory AD

Presnilin 1/2 genes mutation causes loss of function. Crucial in modulation of Ca++ homeostasis and results in cell death.

48

Beta amyloid theory of AD

A-beta is produced from APP, which is cleaved by gamma secretase into 40-42 amino acid fragments. A-beta accumulates into plaques.
Loss of functional Neprilysin which degrades/clears A-beta.

49

AD treatment

Target ACh systems, and use inhibition of AChE, as well as inhibitors of gamma secretase to slow down plaque formation

50

Alzheimer’s Disease (AD) pathology

Loss of cholinergic neurons, plaques,tangles
NTs affected: Ach, 5HT, SST decrease, Glu often increased
1) Beta amyloid theory
2) Tau theory
Loss of neurotransmission (neurotoxicity) leads to dysfunction
Inflammation against plaques and tangles
Age –related changes (loss of SST)

51

Lewy bodies

In all except juvenile early onset parkinsonism -intracellular and extracellular deposits of alpha-synuclein

52

PD symptoms

Movement (tics and difficulty), cognitive and behavioral problems, dementia

53

PD treatments

Levo-DOPA (L-DOPA): Dopamine precursor, prolongs sufficient DA levels
Reuptake inhibitors and use MAO inhibitors
Dopamine agonists: Prolong active signaling
Deep Brain Stimulation
All are short term and do not prevent cell death

54

Late onset PD causes

LRRK2 (PARK8) mutation - overactive kinase domain-hyperphosphorylates a-synuclein, creating Lewy bodies

55

Early onset PD causes

Parkin ligase coded by Parkin2-mutation (autosomal recessive juvenile PD)
part of E3 ubiquitin ligase complex - defective proteosomal degradation of proteins including synuclein, results in toxicity & cell death.

56

Parkinson’s Disease (PD) pathology

Loss of dopaminergic neurons of substantia nigra (degenerates)- motor symptoms

57

Spinobulbar Muscular Atrophy (SMA) (skip)

Symptoms: Loss of anterior horn motor neurons in spinal cord
Affects children to adults
Common genetic cause of childhood death due to breathing and swallowing difficulties
Genes: SMN1 gene or SMN2 gene
Defect in RNA processing machinery
Toxic to motor neurons

58

Transmissible Spongiform Encephalopathies (TSEs)

Infectious proteins (prions) that misfold and accumulate, becoming toxic to neurons and inflammation (vacualization - spongy appearance)

59

Symptoms of TSEs

Bizarre and aggressive behavioral changes
CNS infection leads to degenerative changes
Diagnosed (probable Dx) by brain MRI and symptoms
Confirmed by post morbid brain biopsy

60

Types of TSEs

Creutzfelt-Jacob Disease (CJD)
Bovine TSE- “Mad Cow Disease”
Kuru

61

Stroke/Brain Ischemia

Low to no oxygen and glucose delivery
Causes by blood clots lodged in small vessels, tissue injury or another obstruction (or a ruptured blood vessel (e.g., burst aneurysm) resulting in cell death - VASCULAR)
Blockage of glumate binding sites on NMDA and AMPA receptors can prevent neuron death

62

Genetic causes of cancer of the CNS

Mutations in developmental pathways such as the Sonic Hedgehog receptor system (SHH), such as Patched, as well as transcriptional effector proteins in the same pathway such as cMyc and Gli are also amplified (increased gene copy number and therefore activity) in Medulloblastoma

63

Cytotoxic edema

Affected neurons & glial cells - lack of glucose and oxygen, stops oxidative phosphorylation, cells swell up with water due to ion imbalance (no ATP-driven ion pumps), and cells rapidly die off after oxidative phosphorylation to produce ATP ceases. Neurons die by apoptosis, other by necrosis leaving a dead core of tissue and a spreading wave of depolarization in the periphery of the infarcted area.

64

Vasogenic edema

Radicals degrade vascular walls and increase BBB permeability, loss of astrocytic end feet and permeability to toxic blood proteins such as albumin and access of damage site by inflammatory cells, such as neutrophils.

65

Epilepsy symptoms

General term for recurring seizures (abnormal electrical activity in the brain that causes an involuntary change in body movement or function, sensation, awareness, or behavior)
Can be caused by abnormal medical conditions or genetics

66

Epilepsy genetic causes

Common mutations affect either increased levels of neurotransmitters (e.g., NT processing or reuptake proteins), or specific receptor subunits (ACHRN, GluRA2 etc.) that leading to aberrant activity.

67

Focal epilepsy vs generalized

Isolated in one area of body or brain vs whole body

68

Cancer of CNS growth

Neoplastic changes (mutations) in
Resident/latent CNS progenitors
Dedifferentiation of glia/neurons

69

Cancers of CNS in kids

More prevalent in cerebellum and brain stem (hindbrain) –Medulloblastoma (infratentorial PNET) and other embryonal tumors (supratentorial PNET) or glial (gliomas)
Small highly proliferative non-differentiated tumors that derive form deregulated developmental signaling pathways (Wnt, Sonic Hedgehog(SHH) /patched mutations).
PNET = Primitive neuroectodermal tumor

70

Cancers of CNS in adults

More prevalent in meninges and cerebral hemispheres (glioma) forebrain
Brain: frequent site of metastasis of peripheral cancers due to diminished immune response
BBB breakdown allows influx of immune cells, inflammation
Tumor cells suppress adaptive immune response.

71

Treatment of cancers of CNS

Resection, radiation and chemotherapy
Long term side effects of neuro-cognitive deficits and adverse developmental effects.
Problems: Malignant CNS cancers are intrinsically resistant to therapy, targeting limited by BBB (impervious to (chemotherapy)
Difficulty in diagnosis (cranium)

72

Meningiomas

most common adult primary brain tumor-injury, genetics, NF2

73

Gliomas

Highly vascular gliomas and necrotic core in glioblastoma (hallmark)-worst adult CNS tumor