Neurodegenerative diseases Flashcards
(145 cards)
1
Q
Some neurodegenerative diseases are associated with the degeneration of a particular __ ____, while others cause more widespread degeneration.
A
Cell type
2
Q
Neuronal degeneration is driven by cellular _____,
A
Apoptosis
3
Q
Apoptosis is triggered when _____
A
Clumps of misfolded proteins disrupt normal cellular function.
4
Q
At high enough _______, all proteins have a risk of clumping together.
A
Concentrations
5
Q
Evolution has favored proteins that are _____ to clumping.
A
Resistant
6
Q
What are the 2 steps to correct proteins ?
A
- Protein that is resistant to clumping.
- Protein that folds into a correct 3D shape.
7
Q
True or false : Cells have numerous ways of destroying misfolded protein
A
True
8
Q
Cells have a hard time getting rid of ____ of ____ proteins
A
Aggregates of misfolded proteins
9
Q
Reason misfolded proteins are difficult to break apart by enzymes
A
They are dense and hard to access for enzymes
10
Q
Transmissible spongiform encephalopathy
A
Contagious disease that causes widespread neurodegeneration , making the brain look like a sponge.
11
Q
2 names for Transmissible spongiform encephalopathy
A
Mad cow and Creutzfeldt-Jacob disease
12
Q
Accumulation of this type of misfolded protein is responsible for transmissible spongiform encephalopathies.
A
Prion
13
Q
Prion
A
Misfolded proteins that can cause other copies of the same protein to misfold, which spreads the problem throughout the brain.
14
Q
Number of prion proteins needed to start a chain reaction
A
1
15
Q
_rion protein diseases spread from cell to cell and animal to animal by means of contact with a ____
A
Misfolded prion protein
16
Q
Death from prion protein disease usually occurs within ____
A
a year
17
Q
Only infectious agent that is a protein (does not contain DNA or RNA)
A
Prion protein
18
Q
Huntington’s disease
A
Neurodegenerative disease with a very clear genetic basis. It affects 1 in 10,000 people and runs in families.
19
Q
Cause of Huntington’s
A
A mutation in the Huntingtin gene, which results in misfolding (long version that starts clumping to other proteins) of the huntingtin protein.
20
Q
Is the Huntingtin gene mutation dominant or recessive ?
A
Dominant (one bad copy of the gene).
21
Q
Part of the brain in which Huntingtin protein is highly expressed
A
Basal ganglia.
22
Q
Aggragation of this protein cause parts of the basal ganglia to degenerate
A
Huntingtin protein
23
Q
When do symptoms of Huntington’s start and cause death ?
A
Symptoms usually begin between 30 and 50 years of age. Death follows 15-20 years later
24
Q
4 steps of Huntington’s symptoms progression
A
- Increasingly severe lack of coordination
- uncontrollable jerky limb movements
- dementia
- death.
25
True or false : movements in Huntington's disease may seem voluntary but they are unconscious
True
26
The input nucleus of the basal ganglia that regulates movement receives input from ____ neurons.
Dopamine
27
We each have _ copies of each gene.
2
28
The Huntington gene has a section with more than 39 CAG repeats so the protein is a long version with more than 39 ____ acids in a row.
Glutamine
29
An enzyme tries to cut the amino acid up, but it leaves a ____ (the section with too many glutamine repeats) that is very prone to clumping. It will disrupt cell function.
Fragment
30
Death depends on the ___ of glutamine repeats.
Number (more than 39 means you will die from the disease).
31
A long repeat of the same nucleic acid over and over can be increased because of this.
When a cell is dividing, DNA copying machine can fall off and jump back at the wrong place
32
A possible treatment for protein malformation could be to get the ____ system better at fighting misfolded proteins clumps
Immune
33
Where is antisense DNA (RNA) inserted into in antisense therapy ?
The spinal cord
34
Antisense DNA complements ____
mRNA
35
When antisense DNA an mRNA bind together, the mRNA does not get translated into a ____.
Protein
36
Antisense therapy would allow the ____ protein not to get made in Huntington disease
Long
37
Antisense therapy alters ____ expression
Gene
38
Parkinson's disease
Degenerative “movement” disorder, without an obvious genetic basis (in most instances)
39
Parkinson's results from the degeneration of dopamine neurons in the midbrain, specifically in the ____ _____.
Substancia nigra
40
Parkinson’s disease is very _____, affecting 1% of the population.
Common
41
Symptoms of Parkinson usually appear after the age of ___.
60
42
Reduced dopamine signaling in the basal ganglia leads to ...
Muscle rigidity, slowness of movement, shaking, difficulty walking, and eventually dementia and death.
43
3 types of possible disturbances in Parkinson (other than motor)
Cognitive, emotional, and sleep disturbances
44
For how long can people with Parkinson live ?
15 years
45
Alpha-synuclein is a ____
Protein
46
Where is Alpha-synuclein most expressed ?
Midbrain dopamine neurons
47
Abnormal accumulations of this protein are associated with dopamine neuron degeneration in Parkinson's disease.
Alpha-synuclein
48
Lewy body
Aggregate of misfolded alpha-synuclein protein
49
Where do we find lewy bodies ?
In the cytoplasm of midbrain dopamine neurons in people with Parkinson's disease
50
Rare mutations in the ___ gene have been identified that promote the formation of Lewy bodies.
Alpha-synuclein gene
51
Protein that is added to faulty/old/ misfolded proteins, which targets them for degradation.
Ubiquitin
52
Ubiquitinated proteins get brought to ______, which breaks them into their constituent amino acids for recycling.
Proteasomes
53
Protein that plays a critical role in ubiquitination.
Parkin
54
_____ parkin is one cause of familial Parkinson's disease.
Mutated
55
Proteasome
Organelle responsible for destroying ubiquitinated proteins within a cell.
56
_____ neurons are especially sensitive to loss of parkin function and alpha-synuclein aggregation.
Dopamine
57
If there is a gene mutation in the alpha synuclein protein, the parkin enzyme cannot ____ misfolded alpha-synuclein protein, which will lead to an early onset Parkinson disease.
ubiquitinate
58
Toxic gain of function
When a dominant gene mutation produces a protein with toxic effects.
59
2 examples of toxic gain function
1. Alpha-synuclein gene mutation
2. Mutation in Huntington gene
60
Loss of function
A recessive gene mutation that when present on both chromosomes results in the absence of a necessary protein.
61
Example of loss of function
Mutations in the parkin gene
62
_% of people die from Parkinson
5
63
__% of dopamine neurons need to die for symptoms to get bad.
50
64
When Parkinson symptoms worsen, we need to increase ____ dose
L-Dopa
65
After _ years, L-dopa is hard to dose
5
66
Too much L-dopa can cause too much ____
Movement
67
Elevating _____ signaling in the brain alleviates the motor symptoms of Parkinson’s Disease (for many years).
Dopamine
68
Dopamine receptor ____agonists/antagonists work to some extent, but they cause many side effects
Agonists
69
Does Dopamine cross the blood-brain barrier ?
No
70
Precursor of dopamine that does cross the blood-brain barrier
L-dopa
71
Daily administration of L-dopa can diminish the motor symptoms of Parkinson for many ___.
Years
72
Brain ____ and deep brain stimulation (DBS) can also treat Parkinson
Lesions
73
Main targets for lesions and DBS in Parkinson treatment (parts of the basal ganglia that become overactive)
Globus pallidus and subthalamic nucleus.
74
Damaging the globus pallidus or disrupting subthalamic nucleus activity removes one of the brakes on ____ behaviour.
Motor
75
The entire _____ cortex sends axons into the basal ganglia.
Cerebral
76
The nucleus that receives movements instructions
The caudate nucleus
77
When dopamine neurons die off, the subthalamic nucleus and the globus pallidus internal segments become too _____ inactive/active
Active
78
When dopamine arrives, it tells the subthalamic nucleus and the globus pallidus internal segments to ____stat/stop inhibiting.
Stop
79
Putting a metal wire in the brain and delivering stimulations in the subthalamic nucleus “breaks” it : neurons go into ______polarization/depolarization block.
Depolarization
80
When dopamine stops the subthalamic nucleus and the globus pallidus internal segment from inhibiting, movement is ___initiated/stopped
Innitiated
81
We often implant a battery in the chest to provide continuous energy to always stimulate the ____ nucleus.
Subthalamic
82
Dementia
Progressive impairments to memory, thinking, and behavior due to a neurological disorder that affect one’s ability to perform everyday activities
83
Characteristic of all degenerative diseases.
Dementia
84
Common causes of dementia
Neurodegenerative disease, MS, multiple strokes, and repeated brain trauma.
85
Alzheimer’s disease
Neurodegenerative disorder that causes progressive memory loss, motor deficits, and eventually death.
86
Aggregates of this misfolded protein is present in the brains of people with Alzheimer's disease
β-amyloid protein
87
Amyloid plaque
Extracellular aggregation of β amyloid protein surrounded by glial cells and degenerating neurons
88
Tau protein
Microtubule protein that becomes hyper-phosphorylated in Alzheimer's disease, disrupting intracellular transport.
89
Intracellular accumulation of twisted Tau protein in dying neurons.
Neurofibrillary tangle
90
β-amyloid precursor protein (APP)
Protein that is the precursor for β-amyloid protein. The gene for this protein is located on chromosome 21, which is the one duplicated (triplicated) in down syndrome. It sits in the membrane.
91
Secretase
Class of enzymes that cut the β-amyloid precursor protein into smaller fragments, including β-amyloid
92
Presenilin
Protein that forms part of the secretases that cut APP. Mutations in presenilin can cause it to preferentially generate the abnormal long form of β-amyloid, which causes early onset Alzheimer's disease.
93
Apolipoprotein E (ApoE)
Glycoprotein that transports cholesterol in the blood and plays a role in cellular repair. Presence of the E4 allele of the ApoE gene increases risk of late-onset Alzheimer's disease
94
The ____ cut the β-amyloid protein in 3 fragments.
Secretase enzymes (2)
95
How do the secretase miscut the β-amyloid protein in Alzheimer ?
Some cut it in the wrong spot : 42 amino acids long instead of 40. This long segment is sticky and clumps
96
People with down syndrome have a higher risk of Alzheimer because...
The gene for the precursor β-amyloid protein (APP) is on the chromosome 21.
97
Mutations in the β-amyloid (Aβ) protein due to ____ enzymes; ____or _____ can cause Alzheimer.
Secretase enzymes; presenilin or Apolipoprotein E (ApoE)
98
Other than age, the strongest risk factor for Alzheimer’s disease is...
Traumatic brain injury.
99
Other risk factors of Alzheimer include...
obesity, hypertension, diabetes, and high cholesterol levels
100
Why does high cholesterol make you more likely to develop Alzheimer's ?
A lot of the cell membrane is cholesterol, and at a certain concentration of cholesterol it seems the secretase enzymes are more likely to make the wrong cut.
101
In Alzheimer immunotherapy, we inject antibodies that directly bind to misfolded ____ or ____ protein, marking them for destruction by the immune system.
Aβ protein or Tau protein
102
Amyotrophic lateral sclerosis (ALS) – also known as Lou Gehrig’s Disease and motor neuron disease is a type of _____
Neurodegenerative disorder
103
ALS attacks motor neurons in both the spinal cord and ____ nerves.
Cranial
104
In ALS, proteins aggregates in the ____ neurons will cause them to die off.
Motor
105
Symptoms of ALS
Spasticity (increased muscle tension causing stiff, awkward movements), exaggerated stretch reflexes, progressive weakness and muscular atrophy, followed by paralysis and then death.
106
90% of ALS cases are _____ (unknown cause)
Sporadic
107
ALS disease typically starts after the age of ___.
50
108
Life span with ALS
Life span following a diagnosis is typically 2-4 years, but some people live much longer. For example, Stephan Hawking lived with the disease for over 50 years.
109
Common disease spectrum (FTD–ALS)
Includes ALS and frontotemporal dementia (FTD - another neurodegenerative disorder) in which proteins misfold and spread because of genetic, clinical, and pathological similarities.
110
Prion disease (transmissable), Huntington’s disease (genetic), and ALS-FTD are somewhat ____common/rare.
Rare
111
Parkinson’s and Alzheimer’s are ____common/rare especially with age.
Common
112
There are common gene _____ in the human population that increase people’s risk of getting a specific disorder.
Variants
113
Rare gene mutations usually will be selected ___in/out.
Out
114
Once __% of people have a gene mutation, it is spreading in the human gene pool.
1
115
About 4% of the population has a severe mental illness, and the fertility rate for this group is about ____ the national average.
Half
116
Gene variants that increase your risk of developing a severe physical or mental health issue should get _____ from the gene pool across generations.
Removed
117
Gene mutations arise with each _____.
Generation
118
2 types of gene mutations
1. Different versions of a gene (ex. different versions of an ion channel protein)
2. Different versions of a gene promoter region (changes who and what cell type expresses something).
119
When do we say there are multiple alleles (multiple versions) of a gene ?
When there is gene mutation (both types)
120
If more than 1% of the population has a specific allele (a specific gene variant), this allele is unlikely to be...
Either uniformly beneficial or detrimental to reproductive success
121
Natural selection eliminates _____ genes from the gene pool over time.
Harmful
122
Very harmful gene mutations get quickly eliminated because...
They greatly reduce reproductive success.
123
very harmful gene mutations tend to be rare and ____ in origin.
Recent ( arise anew with each generation but quickly get selected out.)
124
Slightly harmful gene mutations get eliminated more slowly and tend to be inherited across ____ generations (e.g., from great grandparents).
Multiple
125
How harmful are common and old gene mutations ?
Slightly harmful
126
Gene mutations that slightly reduce reproductive success (say by 1%) would only persist in the human gene pool for a ____ before being selected out.
a hundred generations or so (a few thousand years)
127
As harmful alleles get eliminated, the prevalence of ______ alleles increases until everyone gets them.
Beneficial
128
We say a gene has gone to fixation when the same version is found in (nearly) __% of the population.
100
129
f an allele slightly _____ reproductive success (say by 1%), it should spread to the entire population within 100 generations or so
Increases
130
When humans spread into different environmental niches over the last 50,000 years, they experienced rapid changes in...
Skin color, facial characteristics, body shapes, and hair types, among other things
131
Genes mutations from 50,000 years ago spread to everyone and went to fixation (within isolated populations) within ____ years or so.
5000
132
In general, most genes in the human genome have gone to fixation because they promoted _____and _______ in ancestral conditions better than other gene variants did.
Survival and reproduction
133
_____ encoding regions have mostly gone to fixation
Protein
134
____ genes comprise the species-typical human genome, and its normal neurodevelopmental product is human nature
Fixated
135
A variety of alleles are quite ____common/rare
Common
136
Some alleles confer an increased ____ of developing a disease or disorder, while other alleles are protective.
Risk
137
Evolutionary pressure acting on genes
A hundred generations from now, if our environment and lifestyle remain unchanged, the good genes will go to fixation as bad genes get selected out.
138
How did problematic genes persist over the last 200,000 years (10,000 generations) of human history?
Our environment and lifestyles have changed very quickly in recent history.
139
When the environment is stable for hundreds of generations, the only alleles that are maintained are the ones that are beneficial or completely ___ (in that environment).
Neutral
140
The prevalence of neutral alleles drifts ____ across generations
Randomly
141
Many alleles that were neutral or beneficial 50 generations ago are no longer so. They are now _____
Harmful
142
When an allele is neutral in one environment but not another, we say there is a ___- ____interaction.
Gene-environment
143
Disorders associated to environmental factors
Obesity/diabetes, asthma, drug addiction, heart disease/stroke/cancer, late onset neurodegenerative diseases, depression/anxiety
144
Do prevalence rates of schizophrenia and autism vary across cultures or recent history ?
No
145
Severe mental illnesses are mostly ____ and very ____
Heritable and common
