Question

ALS is caused by the accumulation of misfolded protein that eventually leads to neuronal cell death. Just as is the case with prion diseases (e.g., Mad Cow disease), there is a spreading effect: even the presence of a small amount of misfolded (e.g., mutant) protein can cause other WT proteins of the same kind to become misfolded, which join the large misfolded aggregate forming in diseased cells. This is the principle mechanism thought to be behind the spreading of neurodegeneration in the spinal cord: even healthy cells initially not containing mutant protein might take up misfolded protein from the other cells that have died in the vicinity, thus starting the aggregation process anew in what were initially healthy neurons

1. A mutant SOD1 allele has been associated with ALS. SOD1 encodes a protein whose function is to “clean up” oxidative free radicals that are generated primarily from the electron transport chain in mitochondria. Oxidative free radicals are harmful to DNA and proteins and can produce mutations that impact the folding of various proteins in the cell. Accordingly, many ALS patients, as well as mouse models for ALS, show a loss of SOD1 activity and a significant increase in these free radicals. Form a hypothesis as to how SOD1 mutations might lead to ALS. Would you expect a SOD1 mutant allele to be dominant or recessive, and why? Can you imagine a situation where such a SOD1 mutation might be dominant in one patient and recessive in another patient? Explain. Can you imagine why some ALS cases are “sporadic”, as opposed to “inherited”? Explain.

2.

1. Let’s consider a population in which two ALS-causing alleles exist: (i) a hypermorphic TDP43 allele that produces a misfolded TDP43 protein that acts as a “prion” (i.e., causes all TDP43 proteins, even ones without the mutation, to misfold and form protein plaques inside the neuron; (ii) a null SOD1 allele that is less efficient at clearing oxidative free radicals in neurons.

1. Which allele(s) do you expect to be dominant and which do you expect to be recessive? Explain.
2. If one parent has ALS due to a mutant TDP43 gene and a second parent has ALS due to a mutant SOD1 gene, is it certain that their child will also get ALS? What is the probability? Explain.
3. Which of these two parents do you think is more likely to suffer the effects of ALS at an earlier stage in life?
4. In which genetic background(s) might environment and lifestyle be important for preventing the onset of ALS during the course of one’s life?

Answer 1

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hare dominant moole alt with all other in recessire families that of the mutant alleles Axplaination to klould you expect a SODE ... mutant allele to be dom or Recessive and why? Mutation would normally have domina. of inheritance in common wiatt with SODI mutations but that in recessine a tightly linked protective factors act to reduce penetrance of the mutant - Explaination. ?. Can you imagine a situation where such a SODI mutation might be dominant in one pastient and recessive in other patient. Yes of cource the situation of penetrance where exepressivity of the gene can be Seen. Dominat → Complete penetrance Recessive → Incomplete penetrance Explaination 3 This disease opposes to be inherited" rather than to be sporadic because it is caused due to muntation (go-95%) rarely (5-10%) cases are familial. The pattern of inheritance varies depending on the gene involved, very rarely ALS is inherited in an x-linked domint pattern.

e brekessiv dominant @ 9 Here TDP43 gene will be r esson because in hypermorphic condition. gene losses its properties but in few or little but sod1 gene will be recessive bec n null mentation genes loss the. properties and hence has very vess efficiency at clearing oxidative free radicle. en be geres recessive because loss their whole Yes child will also get ALS because TDP43 gene is more efficient dominant Condition for familial ALS disease while Sopt gene is responsible for sporadic Condition of ALS disease here will be 25% chances as probability. Hesse POS Pr Alb eene Alflictelde Here Sodi, mutated gene affected parent will suffer als disease in his/her earlier stage of life because this gehe is responsbibe for sporadic situation of the protein due to the oxidative free radicle in BTS of Mitochondriaa

4 In TDP43 generic condition, the patient might envirnment and life style be important for prevent the onsect of Als, because this gene is responsibe for of familial inheritance Than Thanks (9