Lexture 20 Flashcards
What is the cause of down syndrome?
Inheritance of an extra twenty first chromosome
What is congential?
A disorder that one is born with
What is downsyndrome? Hereditary or congenital?
congenital
What is down syndrome chracterized by?
Moderate to severe intellectual disability and often physical abnornamlities
What happens to people with down syndrome’s brain?
It degenerates in a manner similar to Alzheimers
What is an autoimmune demyelinating disease that usually occurs in people’s late twenties or thirties?
Multiple Sclerosis
What is a sporadic disease?
One that is not obviously caused by inherited gene mutation or an infectious agent
What type of disease is MS?
Sporadic
What happens with MS?
At scattered locations within the central nervous system, myelin sheaths are attacked by the person’s own immune system, leaving behind hard patches of debris called scelortic plaques
What happens in MS people in regards of neural transmission of neural messages?
The transmission of neural messages through demyelinated axons is interrupted
What happens with symptoms of multiple sclerosis? What’s this called?
They go through cycles where they flare up and then decrease after varying periods of time.
Remitting-relapsing MS
What is the pattern of remitting-relapsing MS followed by?
Progressive MS
What is progressive MS charcterized by?
A slow continuous increase in symptoms
Is there yet an effective treatment for MS?
No
What drugs have been found to help MS that can help a little? What are they?
Intereron: a protein that modulates immune system activity
Glatiramer acetate: peptide that mimic myelin (decoy approach)
What people are more likely to get MS? Why?
People who spend their childhood in places far from equator.
It is likely that some disease contracted during childhood spent in region in which virus is prevalent causes person’s immune system to attack his or her own myelin
What is degeneration typically the result of?
Apoptosis
What is apoptosis triggered by?
By collections (aggregates) of misfolded proteins that disrupt normal cellular function
Whats transmissible spongiform encephalopathy?
A contagious brain disease whose degenerative process gives the brain a sponge like appearance
What does transmissible spongeform encephalopathy include?
mad cow disease
What is the accumulation of misfolded prion protein responsible for?
Transmissible spongiform encephalopathies
What are prions?
Misfolded proteins with the ability to transmit their misfolded shape onto normal variants of the same proteins
What happens when a misfolded prion protein interacts with a correctly folded prior protein?
It will cause them to misfold as well
How do prior proteins diseases spread?
From cell to cell and animal to animal by means of contact with misfolded prion protein
What is special about prion protein diseases?
It is the only infectious agent that is just a protein
What do other infectious agents (besides prion proteins) contain?
Nucleic acids
What is huntington’s disease caused by?
A dominant mutation in the huntingtin gene, overtime aggreagtes of huntingtin protein form in the basal ganglia, causing neurodegeneration.
How many people does huntington disease affect?
1 in 10000
At what age do symptoms of huntingtons disease begin?
Death?
Between 30 and 50 years of age.
15-20 years later
What is huntingtons disease chracterized by?
severe lack of coordination, uncontrallable jerky limb movemnts and eventually dementia followed by death
Where is the huntingtin protein heavily expressed?
In the input nuclei of the basal ganglia
What do mutated huntingtin proteins tend to do?
What happens?
Aggregate.
Causes degeneration of neurons in these regions
Is there any cure or treatment for huntingtons?
no
How can antisense DNA or RNA be adminstered
intrathecally (in the spinal cord)
What is another degenerative movemnt disorder?
Parkinsons
What is parkinsons associated with?
Degeneration of dopamine neurons in the midbrain - specifically in the substantia nigra
How much of the population does parkinson’s affect?
1%
When do symptoms of parkinsons appear?
Afer the age of 60
What is parkinson’s charcterized by?
Shaking, muscular rigidity, slowness of movement, difficulty walking and eventually dementia
What happens when people with parkinsons go without treatment?
They have increasing difficulty initiating purposeful movement
What are the causes of parkinson’s disease
Largely unknown
What do the death of midbrain dopamine neurons seem to relate to?
The aggregation of the protein alpha-synuclein
What does the protein alpha synuclein, which is heavily expressed in dopamine neurons tend to do?
What does this cause?
They tend to aggregate
These protein aggregates cauuse dopamine neurons to undergo apoptosis overtime
What does reduced dopamine signaling in the basal ganglia disrupt?
is there a cure?
Movement.
No
What else also develop in parkinsons?
Are there good treatments?
Cognitive, emotional and sleep disturbance.
No
What is a protein that is heavily expressed in midbrain dopamine neurons?
Alpha synuclien
What is the function of alpha-synuclein?
Not clear
What are abnormal accumulations associated with?
Dopamine neuron degeneration in parkinson’s disease
What is the aggregate of misfolded alpha-synuclein protein?
Where is it found?
Lewy body
In the cytoplasm of midbrain dopamine neurons in people with parkinsons disease
What can mutations in the alpha synuclein gene promote?
Can these mutations be dominant?
What does this mean?
Alpha synuclein aggregation, therefore parkinsons disease
Yes
The bad gene only needs to come from one parent
What is ubiquintin?
A protein that is put on faulty/old/misfolded proteins, which targets them for degradation
Where do ubiquitinated proteins get broyght to?
Which?
Proteasomes
Breaks them into their constituent amino acids for recycling
What is parkin?
A protein that plays a critical ubiquitination
What is the cause of familial of parkinson’s disease?
Mutated parkin
What happens if parkin is defective?
Misfolded proteins accumulate, aggreate and eventually kill the cell
What is proteasome?
Organele responsible for destroying ubiquitinated proteins within the cell
What are dopaminerginic neurons especially sensitive to?
A loss of parkin function and alpha synuclein aggregation
What is a genetic disorder caused by a dominant gene mutation that produces a protein with toxic effects?
Toxic gain of function
What is the genetic disorder caused by recessive gene mutation that fails to produce a protein that is necessary to avoid problems?
Loss of function
What are the main symptoms of PD are the result of?
Reduced dopamine signaling
Does dopamine cross the blood brain barrier?
What does this mean?
No.
It cannot be taken as a medecine to boost brain dopamine levels
What are L-dopa treatments?
When the precursor L-dopa can be entered into the brain
What do L-dopa treatments do?
Diminish the motor symptoms of PD
What are common treatments for PD?
Brain lesions
Deep brain stimulation
L-dopa treatments
What are the main targets for lesions and deep brain stimulation?
Parts of the basal ganglia that become overactive in PD: the globus pallidus and subthalamic nucleus
What does damaging the globus pallidus or disruspting subthalamic nucleus activity seems to do?
Relieve parkinson’s disease by removing one of the brakes on motor behaviour
What is the disease chracterized by progressive impairments to memory, thinking and behaviour that affect the ability to perform everyday activities as a result of a neurological disorder?
Dementia
What are common causes of dementia?
neurodegenerative disease
MS
multiple strokes
repeated brain trauma (chronic traumatic encephalopathy)
What is Alzheimer’s disease?
A neurodegenerative disorder that causes progressive memory loss, motor deficits and eventual death
How much of alzheimers occurs in the population above 65?
10%
How much of the population has alzheimers above the age of 85?
50
What is Alzheimer associated with?
Aggregates of misfolded-amyloid protein and severe degeneration within and around the hippocampus and neocortex
Amyloid precursor protein (APP) gene is located where?
In the chromosome 21 (same one duplicated in down syndrome)
What is secretase?
A class of enzymes that cut the amyloid precuror protein into smaller fragments including amyloid
What is the protein that forms part of the secretases that cut APP?
presenilin
What do mutations in presenlin cause?
It to preferentially generate the abnormal long form amyloid which causes early onset Alzhemier’s disease
What is the glycoprotein that transports chlosterol in the blood and plays a role in cellular repair
Apolipoprotein E (ApoE)
What does the presence of the E4 allele of the apoE gene increase of?
Late-onset alzheimer’s disease
What is the protein found in excessive amounts of brain patients with Alzheimer’s disease?
A amyloid
What is amyloid plaque?
Extracellular aggregation of amyloid protein surrounded by glial cells and degenerating neurons
What is tau protein?
A microtubule protein that becomes hyper-phosphorylated in Alzheimer’s disease, disrupting intracellular transport
What is the intracellular accumulation of twisted tau protein in dying neurons?
Neurofibrillary tangle
WHat is the strongest risk factor for alzheimer’s disease besides age?
Traumatic brain injury
What is the impact of lifestyle in alzheimers?
Alzheimers disease is less prevalent in well educated people, especially those that keep their minds and body highly active
Is there a cure for alzheimers?
No but some medications reduce the symptoms a little bit
What are the most promising clinical trials in regards to alzheimers? What do they do?
immunotherapy, to get antibodies to recognize and destroy A protein or tau protein or both
How does the immunotherapy for alzheimer’s patients work?
By sensitizing the patients own immune systems to the proteins or by directly injecting antibodies that are made elsewhere
What is Amyotrophic lateral sclerosis also known as?
Lou Gehrig’s diseas, motor neuron disease or ALS
What is ALS?
Degenerative disorder that attacks spinal cord and cranial nerve motor neurons
What is the incidence of ALS?
3 in 100 000
When does ALS typically start?
After the age of 50
What are the symptoms of ALS?
Spasticity, exageratted stretch reflexes, progressive weakness, muscular atrophy and finally paralysis
How many mutations are usually required to cause the disease?
In two or more genes
Are ALS cases sporadic? How many? What does this mean?
Yes
90 percent
They’re probably new gene mutations
What percent of ALS cases are inherited? Through what gene?
10-20 percent
The mutation in the gene that produces the enzyme superoxide dismutase 1 (SOD1) found on chromosome 21
What is the mutation that causes a toxic gain of function that leads to protein misfolding and aggregation, impaired axonal transport and mitochondrial dysfunction?
The mutation in the gene that produces the enzyme superoxide dismutase 1 (SOD1) found on chromosome 21
What are the ALS and FTD (frontotemporal dementia considered? Why?
Considered to be part of common disease spectrum, because of genetic clinical and pathological similarities
Is there a cure for ALS?
No
What current pharmacological treatment exists for ALS?
A drug that reduces glutamate-induced excitotoxicity, which extends life by about two to three months
What is the average life span following a diagnosis of ALS?
2-4 years, but can be much more (Stephan Hawking)
What are most disorders associated with? What do they have?
Old age
A strong genetic component
What are common gene variants in the human population associated with?
Higher risk of getting a particular late onset disorder
Do harmful gene variants typically get eliminated within a few generations?
Yes
How long do mutations that cause even a slight reduction in fitness persist?
Around 100 generations before being selected out
What does natural selection favour over evolutionary time?
Higher fitness genes
What do most genes in our genome have gone to?
Why?
To fixation
Because they promoted survuval and reproduction under ancestral conditions better than other gened did
What do common gene variants need to be stable across generations?
They must not confer an overall advantage or disadvantge on reproductive succes
What can neutral gene variants give rise to in human nature that are not clearly associated with an overall change in reproductive succes?
variations (like different personality traits)
What happens to gene variants across evolutionary timescales?
gene variants are either selected for or selected against
Why is it likely that some common gene variants that were completely neutral across all ancestral environments are now harmful?
because our environment, culture and life span changed so dramatically
What are the common gene variants that were previously neutral in human history that are now harmful associated with? Example
Associated with disease that show the classic hallmarks of gene environement interaction.
late onset disorders: because we’ve had a rapid increase in human life spans
Are psychiatric illnesses heritable? How much?
Yes
20-80% is explained by genetics
Is psychiatric illness common?How much?
Yes
4%
Are psychiatric illnesses harmful to the reproductive success? How much?
yes
the fertility rate for people with severe mental disorders is about half national average
What have genetic studies discovered about the schizophrenias association with genes?
They are not associated with one bad gene or protein, but rather hundreds of relatively common gene variants each individually confer a very small statistical increase in the risk of developing schizophrenia
What have we discovered about mental illness genes?
That there are no autism genes or bipolar genes, rather hundreds of common gene variants that increase one’s risk of developing some mental illness in general
What is there too much of for mental disorders to qualify as discrete unitary diseases?
too much heterogeneity within diagnostic categories, comorbodity across categories and continuity with normality
What do many of the gene variants associated with ibcreased risk of mental illness regulate?
Brain development and neural plasticity
What do gene variants associated with increased risk of mental illness’s expression in the brain give rise to?
Altered pattens of neural activity throughout the brain
