So if you look under the microscope at the motor neurons of patients who have passed away from ALS, what you’ll see is something called TDP43 pathology. This is a really important protein that is usually located in the nucleus of the cell and is involved in the processing of RNA. And in fact, it processes about a third of all of the RNA that you make in the cell so in dying motor neurons it mislocalizes from the nucleus to the cytoplasm and it’s found in these toxic aggregates in the cytoplasm of the cell and it’s also missing from the nucleus where it’s not doing its job and that leads to widespread dysregulation of RNA and therefore of protein...
So if you look under the microscope at the motor neurons of patients who have passed away from ALS, what you’ll see is something called TDP43 pathology. This is a really important protein that is usually located in the nucleus of the cell and is involved in the processing of RNA. And in fact, it processes about a third of all of the RNA that you make in the cell so in dying motor neurons it mislocalizes from the nucleus to the cytoplasm and it’s found in these toxic aggregates in the cytoplasm of the cell and it’s also missing from the nucleus where it’s not doing its job and that leads to widespread dysregulation of RNA and therefore of protein. And that affects everything in the dying motor neuron from transport up and down the axon to taking out the trash, autophagy, proteasomal degradation, shuttling between the nucleus and the cytoplasm. And these combined effects are neurotoxic. In terms of what causes that TDP pathology to begin with that’s really not known but there are a lot of things that are risk factors that we learn from so age is the biggest risk factor for developing ALS. Additionally repeated head traumas are a risk factor and in fact in chronic traumatic encephalopathy, TDP proteinopathy can be seen in that disorder. It’s a risk factor to be a professional athlete. So playing soccer, football, American football, being an ultramarathon runner, there’s something about repeated sustained anaerobic exercise in the extremes. That’s a risk factor. And particularly for people who are carriers of ALS-causing genes, like C9ORF72 expansions. And they can have earlier onset of disease with extreme exercise. Smoking is a risk factor, especially in postmenopausal women. And there are some toxins that can increase risk, such as certain lawn care products, certain woodworking supplies and things like that. Some exposure to heavy metals, it’s debated, but these are all believed to contribute to risk of ALS. And importantly, genetics plays a role. So in about a quarter of all ALS cases, we can identify a genetic cause that increases someone’s risk of developing ALS.
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