Lecture 20: Neurodegenerative Disorders Flashcards
what causes Down syndrome?
the possession of an extra 21st chromosome
what type of disorder is Down syndrome?
congenital (one is born with it)
symptoms of Down syndrome
moderate to severe intellectual disability and physical abnormalities
neurodegeneration in Down syndrome
After age 30, the brain of a person with Down syndrome begins to degenerate like Alzheimer’s disease
what type of disorder is MS?
sporadic
what is MS?
An autoimmune demyelinating disease that occurs in people’s late 20s or 30s
what causes MS symptoms?
At scattered locations in the CNS, myelin sheaths are attacked by the person’s immune system, leaving hard patches of debris called sclerotic plaques. Normal transmission of neural messages through demyelinated axons is interrupted
cycles of MS symptoms
Symptoms go through cycles of flare-ups and then decrease after varying periods. In most cases, this pattern (remitting-relapsing MS) is followed by progressive MS later in the course of the disease
progressive MS
characterized by a slow, continuous increase in symptoms
who is most likely to get MS?
females who live farther from the equator.
why are people who live father from the equator more likely to get MS
Hygiene hypothesis: It is likely that some diseases contracted during childhood spent in regions where viruses are prevalent cause a person’s immune system to attack their myelin. It is more dangerous to get these viruses as an adult when the immune system gets confused and can cause MS
two treatments approved for MS
Interferon β & Glatiramer acetate
Interferon β:
a protein that modulates immune system activity
Glatiramer acetate
peptides that mimic myelin (decoy approach)
what typically causes neurodegeneration
apoptosis, which is triggered by collections of misfolded proteins that disrupt normal cell function
prion
Misfolded proteins with the ability to transmit their misfolded shape onto normal variants of the same protein
Transmissible spongiform encephalopathy
contagious brain disease (including mad cow disease and Creutzfeldt-Jakob disease) whose degenerative process gives the brain a sponge-like appearance.
what causes transmissible spongiform encephalopathy
Accumulation of misfolded prion protein
what differentiates prion protein disease from other neurodegenerative diseases?
it’s contagious & it’s the only infectious agent that’s just a protein
what causes Huntington’s disease?
Caused by one dominant mutation in the Huntingtin gene. Over time, aggregates of Huntingtin protein form in the basal ganglia, causing neurodegeneration
symptoms of Huntington’s disease
severe lack of coordination, uncontrollable jerky limb movements, and eventually dementia and death
lifespan of people with Huntington’s
Symptoms usually begin between 30-50 and death follows 15-20 years later
what part of the brain degenerates in someone with huntington’s
the basal ganglia
basal ganglia function
help control movements
wild Huntingtin vs. mutation Huntingtin
The wild-type Huntingtin in unaffected people has under 35 glutamines, but the mutation Huntingtin has over 39. This causes long mutant proteins that aggregate and form clumps. Eventually, they get so big that they undergo apoptosis
why do mutant Huntingtin genes keep persisting?
it’s hard to duplicate DNA that has a string of the same letters over and over again.
where is Huntingtin protein heavily expressed?
in the input nuclei of the basal ganglia (the striatum, caudate nucleus, and putamen)
antisense gene therapy
Inject antisense DNA or RNA into the spinal cord (intrathecally) to prevent the affected RNA from being translated into a protein
treatment for Huntington’s
no treatment but some optimism about antisense gene therapy
what causes Parkinson’s disease
combination of genetic and enviornmental factors
neurobiological mechanism of Parkinson’s
Associated with the degeneration of dopamine neurons in the substantia nigra in the midbrain
when do Parkinson’s symptoms appear
after age 60
symptoms of Parkinson’s
muscular rigidity, slowness of movement, difficulty walking, and eventually dementia
what causes the death of dopamine neurons?
aggregation of the protein alpha-synuclein, which eventually causes dopamine neurons to undergo apoptosis
Alpha-synuclein
protein heavily expressed in midbrain dopamine neurons. Its function isn’t entirely clear. Abnormal accumulations are associated with dopamine neuron degeneration in Parkinson’s
Lewy body
an aggregate of misfolded alpha-synuclein protein. Found in the cytoplasm of midbrain dopamine neurons in people with Parkinson’s disease
what type of mutations are alpha-synuclein
dominant
Ubiquitin
Protein that is put on old misfolded proteins, which targets them for degradation. Ubiquitinated proteins get brought to proteasomes, which break them into their constituent amino acids for recycling
Parkin
Protein that plays a critical role in ubiquitination. Mutated Parkin is a cause of familial Parkinson’s disease. If Parkin is defective, misfolded proteins accumulate, aggregate, and eventually kill the cell
Proteasome
Organelle responsible for destroying ubiquitinated proteins within a cell
what type of mutation is Parkin
recessive
toxic gain of function
a genetic disorder caused by a dominant gene mutation that produces a protein with toxic effects
loss of function
a genetic disorder caused by a recessive gene mutation that fails to produce a protein that is necessary to avoid proteins
treatment of Parkinson’s
We can take L-DOPA, a precursor to dopamine, which, when it enters the brain, is readily converted to dopamine
alternative treatment for Parkinson’s
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. This can be done via brain lesions and deep brain stimulation
deep brain stimulation
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
dementia
Progressive impairments to memory, thinking, and behaviour that affects the ability to perform everyday activities as a result of a neurological disorder
Alzheimer’s
a neurodegenerative disorder that causes progressive memory loss, motor deficits, and eventual death
prevalence of Alzheimer’s
This occurs in ~10% of the population above the age of 65 and ~50% of the population above the age of 85
what protein condition is associated with Alzheimer’s
aggregates of misfolded beta-amyloid protein and severe degeneration within and around the hippocampus and neocortex
Beta-amyloid precursor protein (APP)
a protein that is the precursor for the beta-amyloid protein. (The gene for this protein is located on chromosome 21)
secretase
class of enzymes that cut the beta-amyloid precursor protein into smaller fragments including beta-amyloid
presenillin
a protein that forms part of the secretases that cut APP
what happens when there are mutations in presenillin
cause it to preferentially generate the abnormal long-form beta-amyloid, which causes early onset Alzheimer’s disease
Apolipoprotein E (ApoE)
a glycoprotein that transports cholesterol in the blood and plays a role in cellular repair
result of E4 allele of the apoE gene
increases the risk of late-onset Alzheimer’s
Beta-amyloid
Protein found in excessive amounts in the brains of patients with Alzheimer’s
Amyloid plaque
extracellular aggregation of beta-amyloid protein surrounded by glial cells and degenerating neurons
Tau protein
microtubule protein that becomes hyper-phosphorylated in Alzheimer’s disease, disrupting intracellular transport
Neurofibrillary tangle
intracellular accumulation of twisted Tau protein in dying neurons
risk factors for Alzheimer’s
traumatic brain injury, obesity, hypertension, high cholesterol levels, and diabetes
who is LESS likely to get Alzheimer’s
well-educated people
immunotherapy approach for Alzheimer’s
get antibodies to recognize and destroy Beta-amyloid proteins either by sensitizing the patient’s immune system to these proteins or by directly injecting antibodies that are made elsewhere
Amyotrophic Lateral Sclerosis (ALS)
A degenerative disorder that attacks the spinal cord and cranial nerve motor neurons
symptoms of ALS
Symptoms include spasticity (increased tension of muscles, causing stiff and awkward movements), exaggerated stretch reflexes, progressive weakness, muscle atrophy, and finally paralysis
what type of disease is ALS
sporadic
10-20% of ALS cases are caused by ____
a mutation in the gene that produces the enzyme superoxide dismutase 1 (SOD1) found on chromosome 21. This mutation causes a toxic gain of function that leads to protein misfolding and aggregation, impaired axonal transport, and mitochondrial dysfunction
ALS & FTD
ALS and frontotemporal dementia (FTD) are now considered to be part of a common disease spectrum (FTD-ALS) because of genetic, clinical, and pathological similarities
drug treatment for ALS
reduces glutamate-induced excitotoxicity, which extends life by about 2-3 months
average lifespan following an ALS diagnosis
2-4 years
why are late-onset disorders so prevalent
The environmental risk factors associated with late-onset disorders were not present in ancestral environments due to the rapid increase in human lifespan
most genes in the human genome have ___
gone to fixation because they promoted survival and reproduction under ancestral conditions
what genes are schizophrenia associated with?
hundreds of relatively common gene variants, which each create a small statistical increase in the risk of developing schizophrenia
a common theory for the prevalence of schizophrenia
certain combinations of these genes might be advantageous for reproductive success. If this were true, the siblings of schizophrenics who don’t have the disease should have higher reproductive success, but they don’t
