Neurodegenerative Diseases Flashcards
What is a neurodegenerative disease?
A progressive deterioration of brain tissue (mild–> severe) that is accompanied with a decline in functioning, until death
Creutzfeldt-Jakob Disease (CJD) told us a lot about what is driving these diseases. Describe how CJD occurs and what it told us about the infectious nature of proteins.
CJD can be genertic, sporadic or transmitted via infection (eg: tribes in New Guinea)
Standard sterilisation of medical equipment did not prevent the infection. This would denature DNA and RNA and meant that the infectious agent was not a living pathogen.
However, if the sterilisation process denatured proteins the infection was prevented. BUT proteins don’t reproduce themselves…so how could they infect/invade?
Nevertheless, the term “prion” was used for infectious protein.
Creutzfeldt-Jakob Disease (CJD)
We all have _______ proteins (PrP) we manufacture, especially in the nervous system. But these differ between different ______. This explains the species-______ to the transmission of these diseases (eg: sheep form of CJD).
prion
species
barrier
Creutzfeldt-Jakob Disease (CJD)
What was discovered about the two different forms of PrPs? What does this explain about CJD?
We synthesise Prion Proteins and break them down.
- Normal form - degraded by enzymes
- Aberrant form - is not destroyed by enzymes
- -> this is the form that causes the disease.
Animo acid sequences for these are the same, but the folding is dictated by a different genetic code (this explains the genertic form of CJD)
So they both differ in the 3D structure - amino acids are folded differently. Aberrant form is misfolded, and makes it resistance to being broken down by enzymes.
Also, explains the toxicity of the disease.
Creutzfeldt-Jakob Disease (CJD)
The ______ nature of aberrant form of the protein was demonstrated using the mouse form of the disease
- Mice ______ the disease contracted it when injected with material from brains of _______ mice
- But these mice would not get the infection if did not have the _____ _____. They were immune.
This told us that the host has to have ______ PrP present in their body to be ______.
So somehow, the misfolded protein ______ the normally folded protein into the ________ form. And this is the _________ of the infection…it doesn’t reproduce itself, but propagates by converting other proteins.
This put the ______ on proteins and their involvement in other neurodegenerative diseases like Parkinson’s or Alzheimer’s which have some heritability factor and no apparent foreign cause.
infectious without infected PrP gene normal vulnerable converts misfolded mechanism focus
Huntington’s disease is caused by the death of _______ cells in the striatum. It is an autosomal _______ disease. It has been gound that the HTT gene on chromosome 4 codes for the _______ protein. This protein is expressed in all people and is especially high in ______.
However, the gene in those with Huntington’s disease has a ______ DNA sequence on HTT that causes the _______ protein. The protein fragments, when ______-______, get misfolded and the body can’t remove them. For some reason, the GABAerigc neurons are particularly _________.
GABAergic dominant neurons longer mutant/abnormal broken-down vulnerable
In Parkinson’s Disease, a loss of ______ neurons in the ______ _____ is also caused by a misfolded protein called _________. This results in cell death, and the aggravated areas leftover are filled with _____ bodies.
A small, potentially genetic, component of cases have issues with the loss of a protein called ______. This is known to tag proteins that have been misfolded for __________.
alpha‐synuclein
lewy
Parkin
destruction
Alzheimer’s Disease is characterised by a progressive decline in cognitive function. Name the four stages.
- Memory loss (especially recent, autobiographical memory)
- Difficult in word-finding tasks (finding the right words) and complex tasks (especially with steps involved eg: changing a washer)
- Difficulty with simple tasks (eg: feeding) and further language deterioration
- Finally becomes vegetative
What usually causes death in people with Alzheimer’s?
Disease leads to a fragile/weak state. Patient is very unfit and unwell. Often infection/pneumonia takes hold…
___% of all dementia cases are Alzheimer’s Disease. Is it strongly related to ____ (about 40% in their 80s have Alzheimer’s)
50
Alzheimer’s Disease causes widespread loss of brain tissue in the _____. Specifically, there is severe degeneration of ________ and ________ cortex, the _______ cortex (anterior temporal and posterior parietal cortex) and _______ cortex.
Further, there is degeneration of _______ nuclei, such as nucleus basalis (cholinergic), locus ______ (noradrenergic), and _____ nuclei (serotonergic)
Pharmacological treatment tries to increase _________ with AChE inhibitors. This is not a _____. It just improves ________.
cortex hippocampus entorhinal cortex association pre-frontal subcortical coeruleus raphe acetylcholine cure functioning
In post-mortem examinations of brains of Alzheimer’s patients, what two things are seen?
- Senile or amyloid plaques - this is a collection of natural debris (especially beta-amyloid)
- Neurofibrillary tangles - clumps of tau protein
In Alzheimer’s Disease, the senile/amyloid plaques have a significant role in it’s _______. They are made up predominantly from ______ and come from a longer, precursor protein that is part of the cell _____. This precursor protein is usually chopped into ___ pieces by ________ enzymes.
In the normal brain, these pieces are quite _____, and a small amount (10%) are _____. BUT, in Alzheimer’s Disease, up to ____% and in the long form.
pathology beta-amyloid wall 3 secretase
short
long
40
In Alzheimer’s Disease, the neuofibrillary tangles are clumps of ____ protein that are detached from ________ which are part of the neuron’s ________. These essentially ______ the neuron.
tau
microtubules
cytoskeleton
choke
Explain the experiments that illustrate the distribution of the amyloid plaques in Alzheimer’s Disease.
- There is a strong overlap in the distribution of beta-amyloid, and the default network - people not doing anything. This suggests higher activity in the default network might cause or prevent the elimination of these proteins.
