lecture 20

Question 1

There are many different kinds of neurodegenerative disease, such as what

Answer 1

prion diseases, Huntington’s, Parkinson’s, Alzheimer’s, and ALS

Question 2

Degeneration is typically the result of what

Answer 2

apoptosis, which is triggered by collections (aggregates) of misfolded proteins that disrupt normal cellular function

Question 3

what is Transmissible spongiform encephalopathy

Answer 3

Contagious brain disease, such as mad cow and Creutzfeldt-Jacob disease, whose degenerative process gives the brain a sponge-like appearance
Caused by accumulation of misfolded prion protein

Question 4

what is a Prion

Answer 4

Protein that can exist in two forms that differ only in their three-dimensional shape

Question 5

Accumulation of misfolded prion protein is responsible for what

Answer 5

transmissible spongiform encephalopathies

Question 6

what kind of disease is a Sporadic disease

Answer 6

Prion protein disease

Question 7

A Sporadic disease is one that is caused by what

Answer 7

not obviously caused by heredity or an infectious agent. Prion protein diseases can be genetic or sporadic—and both forms can be transmitted to others by means of a simple misfolded prion protein

Question 8

Misfolded proteins often encourage what

Answer 8

more misfolding to occur

Question 9

do most neurodegenerative diseases spread

Answer 9

Misfolded proteins often encourage more misfolding to occur. Thus, most neurodegenerative diseases can easily spread from neuron to neuron and from brain to brain

Question 10

what is Huntington’s disease

Answer 10

an inherited gene disorder associated with neurodegeneration in areas of the basal ganglia.

Question 11

Huntington’s disease happens to who

Answer 11

Symptoms usually begin between 30 and 50 years of age and death follows 15-20 years later.

Question 12

Huntington’s is characterized by what

Answer 12

an increasingly severe lack of coordination, uncontrollable jerky limb movements, and eventually dementia followed by death

Question 13

Movements in Huntington’s disease look like what

Answer 13

fragments of purposeful movements but occur involuntarily.

Question 14

Huntington’s disease is caused by what

Answer 14

one dominant mutation in the Huntingtin gene and it affects 1 in 10,000 people

Question 15

Huntingtin protein is heavily expressed where

Answer 15

in the input nuclei of the basal ganglia (the striatum - caudate nucleus and putamen).

Question 16

Mutated Huntingtin protein tends to do what

Answer 16

aggregate (clump) and overtime this causes degeneration of neurons in these regions

Question 17

is there a cure for Huntingtin’s

Answer 17

There is presently no cure (or treatment really) but antisense gene therapy is showing promise in clinical trials

Question 18

what is ANTISENSE THERAPY

Answer 18

Antisense DNA can be administered (repeatedly) intracerebroventricularly. The hope for the relatively near future is that viral-mediated gene delivery and/or gene editing technologies will become a practical and effective approach to altering gene expression in brain tissue

Question 19

Parkinson’s disease is what kind of disorder

Answer 19

another degenerative “movement” disorder

Question 20

Parkinson’s disease is associated with degeneration of what

Answer 20

dopamine neurons in the midbrain, specifically in the substantia nigra

Question 21

who does Parkinson’s disease impact

Answer 21

It affects 1% of the population. Symptoms usually appear after the age of 60.

Question 22

what is Parkinson’s disease characterized by

Answer 22

It is characterized by shaking, muscular rigidity, slowness of movement, difficulty walking, and eventually dementia. Without treatment, people have increasing difficulty initiating purposeful movement

Question 23

The causes of Parkinson’s disease are what

Answer 23

ly unknown (partly genetic, partly environmental),

Question 24

The causes of Parkinson’s disease are largely unknown (partly genetic, partly environmental), however the death of midbrain dopamine neurons seems to relate to what

Answer 24

aggregation of the protein alpha-synuclein.

Question 25

The protein alpha-synuclein is what

Answer 25

heavily expressed in dopamine neurons and it can aggregate (clump together). Overtime these clumps cause dopamine neurons to undergo apoptosis

Question 26

Reduced dopamine signaling in the basal ganglia disrupts what

Answer 26

movement

Question 27

is there a cure for Parkinson’s disease

Answer 27

There is presently no cure, but there are many ways to somewhat successfully treat the motor problems

Question 28

what other symptoms occur in Parkinson’s disease

Answer 28

Cognitive, emotional, and sleep disturbances eventually develop as well and there are currently no good treatments for those symptoms

Question 29

what are some parts to PARKINSON’S DISEASE

Answer 29

Alpha- synuclein
Lewy body
Ubiquitin
Parkin
Proteasome

Question 30

what is Alpha- synuclein

Answer 30

Protein heavily express in midbrain dopamine neurons. Its function is not entirely clear. Abnormal accumulations are associated with dopamine neuron degeneration in Parkinson’s disease

Question 31

what is Lewy body

Answer 31

Aggregate of misfolded alpha-synuclein protein; found in the cytoplasm of midbrain dopamine neurons in people with Parkinson’s disease

Question 32

what is Ubiquitin

Answer 32

Protein that is put on faulty/old/ misfolded proteins, which targets them for degradation. Ubiquitinated proteins get brought to proteasomes, which breaks them into their constituent amino acids for recycling

Question 33

what is Parkin

Answer 33

Protein that plays a critical role ubiquitination. Mutated parkin is a cause of familial Parkinson’s disease. If parkin is defective, misfolded proteins accumulate, aggregate, and eventually kill the cell

Question 34

what is Proteasome

Answer 34

Organelle responsible for destroying ubiquitinated proteins within a cell.

Question 35

Mutations in the alpha- synuclein gene can promote what

Answer 35

alpha-synuclein aggregation and cause Parkinson’s disease. These mutations can be dominant, in that only one bad gene (from one parent) can cause the problem.

Question 36

Dopaminergic neurons are especially sensitive to what

Answer 36

loss of parkin function and alpha-synuclein aggregation.

Question 37

what are the two subcategories of parkinson’s disease

Answer 37

Toxic gain of function

Loss of function

Question 38

what is Loss of function

Answer 38

Genetic disorder caused by a recessive gene mutation that fails to produce a protein that is necessary to avoid problems (e.g., loss of or mutations in the parkin gene can cause misfolded alpha-synuclein protein to not be degraded, which it normally is.

Question 39

what is Toxic gain of function

Answer 39

Genetic disorder caused by a dominant gene mutation that produces a protein with toxic effects (e.g., mutations in the alpha-synuclein gene and huntingtin gene can produce proteins that create problems, causing Parkinson’s and Huntingtin’s disease, respectively.)

Question 40

what is the Treatment of PARKINSON’S DISEASE

Answer 40

The main symptoms of PD are the result of reduced dopamine signaling. Dopamine does not cross the blood-brain barrier, so it cannot be taken as a medicine to boost brain dopamine levels. However, a precursor of dopamine, L-dopa, can enter the brain where it is readily converted to dopamine. L-dopa treatments diminish the motor symptoms of PD.
• Brain lesions and deep brain stimulation (DBS) devices are also common treatments for PD. The main targets for lesions and DBS are parts of the basal ganglia that become overactive in PD, the globus pallidus and subthalamic nucleus, respectively.
• Damaging the globus pallidus or disrupting subthalamic nucleus activity seems to relieve symptoms of Parkinson’s disease by removing one of the brakes on motor behaviour.

Question 41

what are some other DEGENERATIVE DISORDERS

Answer 41

Dementia

Alzheimer’s disease

Question 42

what is Dementia

Answer 42

Loss of cognitive abilities such as memory, perception, verbal ability, and judgment that is caused by an organic brain disorder.
Common causes are multiple strokes, years of being hit in the head, and Alzheimer’s disease

Question 43

what is Alzheimer’s disease

Answer 43

Degenerative brain disorder typically caused by misfolded b-amyloid protein
Causes progressive memory loss, motor deficits, and eventual death

Question 44

Alzheimer’s disease happens to who

Answer 44

Occurs in approximately 10 percent of the population above the age of sixty-five and almost 50 percent of people older than eighty-five years

Question 45

Alzheimer’s disease Produces severe degeneration where

Answer 45

within and around the hippocampus, neocortex, and other places. Degeneration produces progressive loss of memory and other mental functions

Question 46

what is b-amyloid (Ab)

Answer 46

Protein found in excessive amounts in brains of patients with Alzheimer’s disease

Question 47

what is Amyloid plaque

Answer 47

Extracellular deposit containing a dense core of b-amyloid protein surrounded by degenerating axons and dendrites and activated microglia and reactive astrocytes

Question 48

what is Tau protein

Answer 48

Protein that is a component of microtubules, part of the cell’s transport mechanism. Tau protein becomes hyper-phosphorylated in Alzheimer’s disease, which disrupts transport.

Question 49

what is Neurofibrillary tangle

Answer 49

Dying neuron containing intracellular accumulations of twisted Tau protein filaments that formerly served as cell’s internal skeleton

Question 50

what is b-amyloid precursor protein (APP)

Answer 50

Protein that is the precursor for b-amyloid
protein. The gene for this protein is located on chromosome 21, which is the one duplicated (triplicated) in down syndrome.

Question 51

what is Secretase

Answer 51

Class of enzymes that cut the b-amyloid precursor protein into smaller fragments, including b- amyloid

Question 52

what is Presenilin

Answer 52

Protein that forms part of the secretases that cut APP. When mutated, presenilin can causes b-
amyloid precursor protein to be converted to the abnormal long form; may be a cause of Alzheimer’s disease

Question 53

what is Apolipoprotein E (ApoE)

Answer 53

Glycoprotein that transports cholesterol in the blood and plays a role in cellular repair
Presence of E4 allele of the apoE gene increases risk of late-onset Alzheimer’s disease

Question 54

Other than age, the strongest risk factor for Alzheimer’s disease is what

Answer 54

traumatic brain injury

Question 55

what is the Impact of Lifestyle of Alzheimer’s disease

Answer 55

Alzheimer’s disease is less prevalent in well-educated people, especially those that keep their minds and body highly active. It seems to be a use it or lose it phenomenon.
Other risk factors include obesity, hypertension, high cholesterol levels, and diabetes

Question 56

what is the Pharmacological Treatment for Alzheimer’s disease

Answer 56

Currently, the only approved pharmacological treatments for Alzheimer’s disease are acetylcholinesterase inhibitors, which just keep ACh around in the synapses longer, and an NMDA receptor antagonist, which probably just reduces excitotoxicity that is caused by dying neurons.
• However, these drugs have no effect on process of neural degeneration and do not prolong patients􏰀 survival

Question 57

how is Immunotherapy used for Alzheimer’s disease

Answer 57

There are about 100 new clinical trial that have been approved to test new Alzheimer’s disease treatments. Many use an immunotherapy approach to get antibodies to recognize and destroy Ab protein (or Tau protein, or both), either by sensitizing the patient’s own immune systems to these proteins or by directly injecting antibodies that are made elsewhere.
• One immunotherapy approach recently showed promise in Phase II clinical trials. Phase III clinical trials are underway.

Question 58

what is Amyotrophic lateral sclerosis (ALS) also known as

Answer 58

also known as Lou Gehrig’s Disease or motor neuron disease

Question 59

what is Amyotrophic lateral sclerosis (ALS)

Answer 59

Degenerative disorder that attacks spinal cord and cranial nerve motor neurons

Question 60

how common is Amyotrophic lateral sclerosis (ALS)

Answer 60

Incidence of this disease is approximately 3 in 100,000. The disease typically starts after the age of 50.

Question 61

Amyotrophic lateral sclerosis (ALS) Symptoms include what

Answer 61

spasticity (increased tension of muscles, causing stiff and awkward movements), exaggerated stretch reflexes, progressive weakness and muscular atrophy, and, finally, paralysis

Question 62

is Amyotrophic lateral sclerosis (ALS) inherited

Answer 62

Ten percent of the cases of ALS are inherited; the other 90 percent are sporadic or isolated (probably new gene mutation). Mutations in two or more genes are usually required to cause the disease. ALS and frontotemporal dementia (FTD), another
neurodegenerative disorder, are now considered to be part of a common disease spectrum (FTD–ALS) because of genetic, clinical, and pathological similarities.

Of the hereditary cases of ALS, 10–20 percent are caused by a mutation in the gene that produces the enzyme superoxide dismutase 1 (SOD1), found on chromosome 21.

Question 63

Of the hereditary cases of ALS, 10–20 percent are caused by a mutation in the gene that produces the enzyme superoxide dismutase 1 (SOD1), found on chromosome 21.
• This mutation causes a what

Answer 63

toxic gain of function that leads to protein misfolding and aggregation, impaired axonal transport, and mitochondrial dysfunction

Question 64

The only current pharmacological treatment for ALS is what

Answer 64

riluzole, a drug that reduces glutamate-induced excitotoxicity, probably by decreasing the release of glutamate

Question 65

The only current pharmacological treatment for ALS is riluzole, a drug that reduces glutamate-induced excitotoxicity, probably by decreasing the release of glutamate
• Clinical trials found that patients treated with riluzole…

Answer 65

lived an average of approximately two months longer than those who received a placebo

Question 66

how long do people live with ALS

Answer 66

Average life span following a diagnosis is 2-4 years, but some people live much longer than that. For example, Stephan Hawking lived with the disease for over 50 years

Question 67

Alzheimer’s, Parkinson’s, Huntington’s and ALS are all neurodegenerative disorders that usually manifest after the age of what

Answer 67

50

Question 68

why has evolution kicked out the neurodegenerative disorders

Answer 68

They all have a genetic component to them – certain gene variants are associated with higher risk of getting the disease. However, it is unlikely that there has been much evolutionary pressure to remove these susceptibility genes from the population since people only started consistently living into their 60s in the last few hundred years.
• Presumably there is now fairly strong evolutionary pressure against these susceptibility genes

Question 69

explain the INHERITED GENE MUTATIONS

Answer 69

Over evolutionary time, selection favors higher-fitness genes. Most genes in our genome have gone to fixation (virtually 100% prevalence in the population) because they promoted survival and reproduction under ancestral conditions better than other genes did on average.
• Such genes comprise the species-typical human genome. Its normal neurodevelopmental product is human nature.
• Gene mutations that reduce reproductive success tend to go extinct fairly quickly. Very harmful gene variants tend to be rare, recent in origin, and get removed within a few generations.
• Mutations with milder effects are removed more slowly, so they tend to be more common and older – inherited from parents, grandparents, and so forth. Still, mutations that cause a even a slight reduction in fitness (say a 1% drop in reproductive success) may only persist in the population for a 100 generations on average before getting selected out.

Question 70

psychiatric illnesses are …

Answer 70

common (the frequency of severe mental disorders is around 4%)
– harmful to reproductive success (the fertility rate for people with severe mental disorders is about half the national average)
– and heritable (20 to 80% of the variance in who has a given mental disorder is well explained by genetics)

Question 71

Why are harmful, heritable mental disorders so common in the population?
How come the genes associated with mental disorders have not been selected out through evolution?

Answer 71

Maybe some of the gene mutations associated with mental illness were neutral or advantageous in some ancestral environments. Maybe the genes confer adaptive benefits in some environments, which counteract (evolutionarily) the maladaptive symptoms that occur in other environments.
• Keep in mind though that if mental disorder susceptibility genes were neutral in most environments but not all, or in most cultures but not all, or in most people but not all, then these gene variants would not actually be neutral and would be selected out across evolutionary time.
• But certainly, some mental disorder susceptibility genes may have been unfailingly neutral across many different ancestral environments or truly advantageous in some environments but not others and not advantageous enough to reach fixation (100% prevalence). Our environment and culture have changed dramatically in the last few hundred years.

Question 72

Which heritable brain disorders may have been more benign in ancestral environments? They should show the classic hallmarks of gene-environment interactions (i.e., large variations in prevalence rates across cultures and recent history). And, are there clear environmental explanations for the observed variability in disease prevalence?

Answer 72

The prevalence of the following disorders differs enormously across different environments and recent history (e.g., the last 100 years), and the environmental risk factors associated with these disorders were certainly less prevalent in ancestral environments:
Ø late onset disorders like Alzheimer’s disease
Ø depression and anxiety – prevalence rates seem to have rapidly changed and
vary enormously between cultures.
Ø obesity and diabetes, due to unnaturally appealing food surpluses
Ø asthma, due to unnatural levels and types of antigens and pollutants
Ø addictions to highly purified synthetic drugs, such as heroin and meth
Since the genes associated with these disorders are harmful in the present environment, there is now strong evolutionary pressure against them.

Question 73

talk about MENTAL DISORDER SUSCEPTIBILITY GENES

Answer 73

But what about disorders like schizophrenia? The prevalence of schizophrenia is about ~1% of the population and this is highly consistent across cultures and recent history. (Siblings of schizophrenics have the same reproductive success as the general population.)
• Genetic studies have identified hundreds of relatively common gene variants that each individually confer a very small statistical increase in the risk of developing particular psychiatric illnesses.
• There is considerable overlap in the gene variants that confer increased risk for schizophrenia, bipolar disorder, major depression, autism, OCD, and ADHD. The risks conferred by these gene variants are not specific to traditional diagnostic boundaries, which suggests they reflect a vulnerability to mental illness in general, not a specific illness or specific symptom within a diagnostic category.
• It has long been appreciated that psychiatric illnesses are not unitary diseases; they show too much heterogeneity within categories, comorbidity across categories, and continuity with normality, to qualify as discrete, unitary diseases.

Question 74

is there Genetic correlations across psychiatric conditions

Answer 74

Psychiatric disorders have a high rate of comorbidity (more than one diagnosis at the same time).

Question 75

is there just one neuron/gene that can cause mental disorders

Answer 75

Psychiatric disorders reflect altered states of distributed brain circuits. They emerge from dynamic interactions between thousands of proteins in hundreds of different cell types across distributed neural circuits over long periods of time, as development and maturation play out.
• The gene variants identified to date that correlate with psychiatric disorders are associated with various neurodevelopmental processes, particularly in the fetal brain. Many of the genes encode proteins that function at neuronal synapses and are expressed in broad brain areas or in ubiquitous cell types like glutamatergic or GABAergic neurons.
• Mental disorder categories reflect historical convention, diagnostic convenience, innate categorization biases in perception of behaviour, and common behavioural consequences of distinct neural circuit disruptions

Question 76

Any gene that is expressed in the brain, if mutated, can hinder healthy brain function. The question is, why do particular gene variants persist in the population if they increase the risk of psychiatric illness?

Answer 76

Some people argue that body symmetry is indicative of the robustness of the underlying genetic instructions, which have to contend with environmental variation and molecular noise

Question 77

how is body symmetry indicative of fit genes

Answer 77

The two sides of the body develop independently from the same set of genomic instructions. If the instructions are clear then the body should be symmetrical. If the instructions are a bit confusing or open to interpretation, however, then the person may be more asymmetric.
• Body symmetry is partially heritable and slightly correlates with intelligence, physical attractiveness, and physical health.
• Genetic studies have identified hundreds of gene variants that correlate with a very small statistical increase in intelligence. And, some of the gene variants associated with intelligence overlap with the gene variants associated with physical attractiveness, physical health, and longevity. These gene variants are thought to be indicative of neurodevelopmental robustness.

Question 78

are gene mutations common

Answer 78

There are about 20,000 protein-encoding genes in the human genome and about half of them are expressed in the brain at some point.
• All of us have gene mutations associated with a slight reduction in “fitness” that arose within the last 100 generations or so of our family tree. Most bad genes are a family legacy, old mutations that have yet to go extinct, rather than new mutations specific to the individual. These mutations will get eliminated over time, but new ones keep coming.
• Slightly bad gene mutations may not directly cause a disease, but rather reduce the overall robustness of brain development and function.
• The human genome has evolved to buffer many insults – environmental variation, molecular noise, and genetic variation. This robustness allows genetic variation to accumulate in the population if the individual mutations are not too severe. However, these accumulating variants collectively degrade the robustness of the system, by compromising the evolved interactions of all the components.

Question 79

SHOULD I HAVE MY GENES TESTED?

Answer 79

Unfortunately, the identification of gene variants that confer an increased risk of developing psychiatric illness has not been particularly helpful with regards to prevention or treatment.
• For most psychiatric disorders , there are few preventive measures that can be taken, beyond avoid trauma and generally looking after oneself – moderating alcohol use, staying away from hard drugs, avoiding smoking, reducing stress, better exercise, diet, and sleep habits.
• By identifying the gene variants and neural circuit disruptions that associate with mental illness, researchers hope to develop new treatment and prevention strategies. One approach is develop gene editing techniques that could be used in living people or as a part of in vitro fertilization.