Kudos to your doctor friend @adreamer.
It's all above my pay grade, but my pet AI robot seems to like it!
Your comments reflect a solid grasp of the complex interrelations between genetic factors and different neurodegenerative diseases, particularly as they pertain to ALS (Amyotrophic Lateral Sclerosis), SBMA (Spinal and Bulbar Muscular Atrophy), and related cellular mechanisms. Here's a breakdown to verify and expand on the accuracy of the observations made in your comments:
1. **SBMA and ALS Connection**: Your understanding that SBMA is caused by a mutation in the androgen receptor gene, which involves an elongated polyglutamine tract (ARpolyQ), is accurate. The current scientific consensus does not establish a direct link between ARpolyQ toxicity and bulbar onset ALS. This distinction is important as SBMA and ALS, while both motor neuron diseases, have distinct genetic and pathological profiles.
2. **Proteasome and Autophagy in SBMA**: The information regarding the role of proteasomes and autophagy in degrading ARpolyQ aggregates in the context of SBMA, based on studies in NSC34 cells, is correctly represented. It's important to note that findings in cell models, such as NSC34, might not directly translate to in vivo conditions, including those for bulbar onset ALS. This difference in contexts highlights why cellular mechanisms observed in one disease (like SBMA) might not necessarily apply to another (such as ALS).
3. **Clinical Trials and Exclusion Criteria**: Your analysis of the exclusion criteria in the clinical trial (NCT04894240) is insightful. The exclusion of patients with SOD1 mutations in ALS studies is notable because SOD1-associated ALS can exhibit distinct pathological and clinical characteristics compared to more typical forms of the disease, primarily marked by the absence of TDP-43 pathology, which is commonly found in other forms of ALS.
4. **VCP and Neurodegeneration**: The information you've reviewed about VCP (Valosin Containing Protein) and its link to both Frontotemporal Dementia (FTD) and ALS is accurate. VCP mutations underscore the genetic overlap between these neurodegenerative diseases, highlighting the shared pathways in their neuropathology.
5. **Concerns about MPL (Monepantel) in Bulbar ALS**: Your conclusion about the potential efficacy of MPL in treating bulbar ALS, despite the complexities and distinctions between different forms of ALS, indicates a thoughtful consideration of how molecular targets may differ across subtypes of a disease. It’s a prudent approach to be cautious and considerate about extending findings from one ALS subtype to another without clear evidence.
In summary, your comments are well-informed and align with current scientific understanding. The cautious approach to extrapolating findings across different conditions and the nuanced understanding of the genetic aspects of neurodegenerative diseases are particularly commendable.
I'll leave all the science to those who know science! (But thanks for sharing and @kpax too - very interesting indeed!)
Cheers
Densy
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