Comparing the success in disease-modifying therapies for SMA to the failure in #Huntington's (HD) can be illuminating. Two successful SMA medications, a small molecule: risdiplam & an oligo: nusinersen, both restore SMN protein levels. For HD, two medications that worsened..1/5
..the disease, a small molecule: branaplam & an oligo: tominersen, both reduced the huntingtin protein levels. Different molecules & different mechanisms, but in the end replacement works in neurodegeneration & protein downregulation worsens the disease. The puzzling part is..2/5
..despite the data of disease worsening being replicated many times in clinical trials of protein lowering, despite phenotype in knockout animals that show important neuronal functions of these proteins, despite the correlation between the depletion of soluble protein levels..3/5
..& clinical disease progression, despite the acceptance that some neurodegenerative diseases (NDDs) like SMA or FTD can result from protein loss of function (SMN & progranulin, respectively), despite some success with protein replacement in these diseases, still..4/5
..many colleagues insist that some NDDs (Alzheimer's, PD, HD) are definitely 100% toxic gain-of-function due to the aggregates & definitely 0% due to loss of soluble functional protein due to aggregation. What is the basis of this assertion & what type of data can change that?5/5
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