Exam Revision Flashcards
What is ALS?
Amyotrophic lateral sclerosis- adult onset fatal neuronal disorder characterised by the progressive loss of upper and lower motor neurons; currently has no cure
What is the epidemiology of ALS?
affects about 2 in 100,000 people
most patients are over 40 yoa
Most people die between 2-5 years of onset, but some die within months and others can live up to 20 years
Men have a greater risk than females
Associated with risk factors such as smoking and excessive exercise
Most cases are sporadic, but few cases are familial (10%).
What is SOD1?
Genetic mutation associated with 20% of people with familial ALS and 2-3% of cases of SALS.
Superoxide dismutase 1 is a protein associated with free-radical scavenging and almost all mutations in this gene are dominant (except one Scandinavian strain)
Almost all mutations are mis-sense mutations, but some truncated mutations at the C-terminal have been reported
How does a mutation in SOD1 cause ALS?
When SOD1 misfolds, it is targeted for degredation by ubiquitination but seems to escape the regulatory process. The mutant protein is misfolded and causes endoplasmic reticulum stress by overloading the unfolded protein response, disrupting mitochondria and axonal transport. This leads to axonal retraction and death
What is TDP43?
Another prevalent mutation known to cause ALS; mutation in TARBP which encodes the protein TDP43. Almost all mutations are in exon6 of TARBP- mostly missense mutations.
What is the normal function of TDP43?
Normal function is for transcription, RNA splicing and transport. Needs to move between the nucleus and cytoplasm as it transports RNA which is silenced to the axon where it can be translated.
How does TDP43 cause disease?
When the cell undergoes stress due to high temperature or damage, TDP43 is incorporated into stress granules until the stress is dealt with. In these granules, there is a pro-aggregation environment. TDP43 aggregates in these granules in the cytoplasm. Gives rise to a loss and gain of function, where the nucleus is without TDP43 and the cytoplasm has too much in aggregate form.
How does C9ORF72 cause FALS?
Function of this protein is currently unknown, but the gene is encoded on chromosome 9 and a mutation is correlated with ALS. Expanded repeats of GGGGCC can be seen at the hexonucleotide region and patients with ALS have thousands of these repeats, whereas normal people have 2-30 repeats. This expansion is thought to cause flawed RNA transcripts, which prevent the translation of protein and change gene expression in the cell.
Where are interaural time differences coded in the mammalian brain?
In the medial superior olive
Where are interaural level differences coded in the mammalian brain?
In the lateral superior olive.
