lecture 20 Flashcards
There are many different kinds of neurodegenerative disease, such as what
prion diseases, Huntington’s, Parkinson’s, Alzheimer’s, and ALS
Degeneration is typically the result of what
apoptosis, which is triggered by collections (aggregates) of misfolded proteins that disrupt normal cellular function
what is Transmissible spongiform encephalopathy
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
what is a Prion
Protein that can exist in two forms that differ only in their three-dimensional shape
Accumulation of misfolded prion protein is responsible for what
transmissible spongiform encephalopathies
what kind of disease is a Sporadic disease
Prion protein disease
A Sporadic disease is one that is caused by what
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
Misfolded proteins often encourage what
more misfolding to occur
do most neurodegenerative diseases spread
Misfolded proteins often encourage more misfolding to occur. Thus, most neurodegenerative diseases can easily spread from neuron to neuron and from brain to brain
what is Huntington’s disease
an inherited gene disorder associated with neurodegeneration in areas of the basal ganglia.
Huntington’s disease happens to who
Symptoms usually begin between 30 and 50 years of age and death follows 15-20 years later.
Huntington’s is characterized by what
an increasingly severe lack of coordination, uncontrollable jerky limb movements, and eventually dementia followed by death
Movements in Huntington’s disease look like what
fragments of purposeful movements but occur involuntarily.
Huntington’s disease is caused by what
one dominant mutation in the Huntingtin gene and it affects 1 in 10,000 people
Huntingtin protein is heavily expressed where
in the input nuclei of the basal ganglia (the striatum - caudate nucleus and putamen).
Mutated Huntingtin protein tends to do what
aggregate (clump) and overtime this causes degeneration of neurons in these regions
is there a cure for Huntingtin’s
There is presently no cure (or treatment really) but antisense gene therapy is showing promise in clinical trials
what is ANTISENSE THERAPY
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
Parkinson’s disease is what kind of disorder
another degenerative “movement” disorder
Parkinson’s disease is associated with degeneration of what
dopamine neurons in the midbrain, specifically in the substantia nigra
who does Parkinson’s disease impact
It affects 1% of the population. Symptoms usually appear after the age of 60.
what is Parkinson’s disease characterized by
It is characterized by shaking, muscular rigidity, slowness of movement, difficulty walking, and eventually dementia. Without treatment, people have increasing difficulty initiating purposeful movement
The causes of Parkinson’s disease are what
ly unknown (partly genetic, partly environmental),
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
aggregation of the protein alpha-synuclein.
The protein alpha-synuclein is what
heavily expressed in dopamine neurons and it can aggregate (clump together). Overtime these clumps cause dopamine neurons to undergo apoptosis
Reduced dopamine signaling in the basal ganglia disrupts what
movement
is there a cure for Parkinson’s disease
There is presently no cure, but there are many ways to somewhat successfully treat the motor problems
what other symptoms occur in Parkinson’s disease
Cognitive, emotional, and sleep disturbances eventually develop as well and there are currently no good treatments for those symptoms
what are some parts to PARKINSON’S DISEASE
Alpha- synuclein Lewy body Ubiquitin Parkin Proteasome
what is Alpha- synuclein
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
what is Lewy body
Aggregate of misfolded alpha-synuclein protein; found in the cytoplasm of midbrain dopamine neurons in people with Parkinson’s disease
what is Ubiquitin
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
what is Parkin
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
what is Proteasome
Organelle responsible for destroying ubiquitinated proteins within a cell.
Mutations in the alpha- synuclein gene can promote what
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.
Dopaminergic neurons are especially sensitive to what
loss of parkin function and alpha-synuclein aggregation.
what are the two subcategories of parkinson’s disease
Toxic gain of function
Loss of function
what is Loss of function
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.
what is Toxic gain of function
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.)
what is the Treatment of PARKINSON’S DISEASE
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.
what are some other DEGENERATIVE DISORDERS
Dementia
Alzheimer’s disease
what is Dementia
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
what is Alzheimer’s disease
Degenerative brain disorder typically caused by misfolded b-amyloid protein
Causes progressive memory loss, motor deficits, and eventual death
Alzheimer’s disease happens to who
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
Alzheimer’s disease Produces severe degeneration where
within and around the hippocampus, neocortex, and other places. Degeneration produces progressive loss of memory and other mental functions
what is b-amyloid (Ab)
Protein found in excessive amounts in brains of patients with Alzheimer’s disease
what is Amyloid plaque
Extracellular deposit containing a dense core of b-amyloid protein surrounded by degenerating axons and dendrites and activated microglia and reactive astrocytes
what is Tau protein
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.
what is Neurofibrillary tangle
Dying neuron containing intracellular accumulations of twisted Tau protein filaments that formerly served as cell’s internal skeleton
what is b-amyloid precursor protein (APP)
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.
what is Secretase
Class of enzymes that cut the b-amyloid precursor protein into smaller fragments, including b- amyloid
what is Presenilin
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
what is Apolipoprotein E (ApoE)
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
Other than age, the strongest risk factor for Alzheimer’s disease is what
traumatic brain injury
what is the Impact of Lifestyle of Alzheimer’s disease
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
what is the Pharmacological Treatment for Alzheimer’s disease
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
how is Immunotherapy used for Alzheimer’s disease
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.
what is Amyotrophic lateral sclerosis (ALS) also known as
also known as Lou Gehrig’s Disease or motor neuron disease
what is Amyotrophic lateral sclerosis (ALS)
Degenerative disorder that attacks spinal cord and cranial nerve motor neurons
how common is Amyotrophic lateral sclerosis (ALS)
Incidence of this disease is approximately 3 in 100,000. The disease typically starts after the age of 50.
Amyotrophic lateral sclerosis (ALS) Symptoms include what
spasticity (increased tension of muscles, causing stiff and awkward movements), exaggerated stretch reflexes, progressive weakness and muscular atrophy, and, finally, paralysis
is Amyotrophic lateral sclerosis (ALS) inherited
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.
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
toxic gain of function that leads to protein misfolding and aggregation, impaired axonal transport, and mitochondrial dysfunction
The only current pharmacological treatment for ALS is what
riluzole, a drug that reduces glutamate-induced excitotoxicity, probably by decreasing the release of glutamate
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…
lived an average of approximately two months longer than those who received a placebo
how long do people live with ALS
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
Alzheimer’s, Parkinson’s, Huntington’s and ALS are all neurodegenerative disorders that usually manifest after the age of what
50
why has evolution kicked out the neurodegenerative disorders
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
explain the INHERITED GENE MUTATIONS
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.
psychiatric illnesses are …
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)
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?
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.
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?
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.
talk about MENTAL DISORDER SUSCEPTIBILITY GENES
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.
is there Genetic correlations across psychiatric conditions
Psychiatric disorders have a high rate of comorbidity (more than one diagnosis at the same time).
is there just one neuron/gene that can cause mental disorders
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
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?
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
how is body symmetry indicative of fit genes
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.
are gene mutations common
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.
SHOULD I HAVE MY GENES TESTED?
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.
