Vuonna 2015 johtopäättelin, että (TDP-43-)ALS johtuu häiriintyneestä stressigranulidynamiikasta. Kysyin ChatGPT:n mielipidettä:
If your hypothesis is “ALS involves persistent stress granules (SGs) that fail to disassemble and seed pathology,” here’s the tight read:
Normally, SGs assemble under acute stress and disassemble minutes–hours after stress relief. In ALS models, SGs linger (reduced dynamics, slower clearance) and enrich TDP-43/FUS, creating a path to insoluble aggregates. (PMC, Nature)
“Persistent SGs” is a plausible and testable mechanistic slice of ALS: chronic or dysregulated SGs can become sticky waystations that recruit and convert TDP-43/FUS toward pathology. Your hypothesis fits current evidence best when framed as:
If you want, I’ll sketch the exact imaging/analysis pipeline (markers, timepoints, FRAP settings, stats) so it’s plug-and-play for an iPSC MN experiment.
If your hypothesis is “ALS involves persistent stress granules (SGs) that fail to disassemble and seed pathology,” here’s the tight read:
What “persistent SGs” means
Normally, SGs assemble under acute stress and disassemble minutes–hours after stress relief. In ALS models, SGs linger (reduced dynamics, slower clearance) and enrich TDP-43/FUS, creating a path to insoluble aggregates. (PMC, Nature)
Evidence that persistence is real (and harmful)
- C9orf72 DPRs (especially arginine-rich) disrupt SG assembly/dynamics and aggravate SG pathology. (PMC, pnas.org)
- ATXN2 intermediate polyQ expansions (Q27–33 range)—a strong ALS risk factor—enhance stress-induced TDP-43 changes and tie SG biology to disease risk. Lowering ATXN2 is protective in models. (PMC, Neuroscience, Nature)
- Chronic stress paradigms better recapitulate TDP-43/SG phenotypes than acute stress, consistent with prolonged SG presence. (PMC)
- Mechanistic links to TDP-43 pathology: SGs concentrate TDP-43, and recent work shows demixing/maturation inside SGs can generate pathological TDP-43; preventing that demixing eliminates aggregates in cells. (cell.com, ScienceDirect)
Counterpoints/nuance
- Some data suggest SG formation can be initially protective, and in certain contexts SG competence is impaired. The emerging consensus is not “more SGs good/bad,” but maladaptive persistence/maturation is bad. (Oxford Academic)
Test the “persistence” idea cleanly
- Kinetics assay: In iPSC motor neurons (ALS vs controls), induce SGs (e.g., sodium arsenite), washout, quantify clearance half-life of SG markers (G3BP1/TIAR) by live imaging; add FRAP to measure internal dynamics. Expect longer half-life & slower recovery in ALS lines. (PMC)
- Cargo fate: Track TDP-43 partitioning in/after SGs (biochemistry + microscopy) and test if persistent SGs predict insoluble, phosphorylated TDP-43 at later time points. (Nature)
- Genetic modifiers: Knock down ATXN2 or express C9orf72 DPRs to bidirectionally shift persistence; see if TDP-43 pathology follows. (Nature, pnas.org)
- Clearance pathways: Inhibit/activate autophagy/UPS and measure SG persistence to pinpoint failed resolution steps. (Rationale from SG turnover literature.) (PMC)
Therapeutic angle (proof-of-concept)
- Condensate-modifying small molecules (e.g., lipoamide/lipoic acid) reported to prevent or dissolve SGs and reduce aggregation in models; recent peer-reviewed work strengthens this line, though it’s still preclinical. Use them as pharmacologic probes for your persistence assay. (Nature, PubMed, BioRxiv, Science, PMC)
Bottom line
“Persistent SGs” is a plausible and testable mechanistic slice of ALS: chronic or dysregulated SGs can become sticky waystations that recruit and convert TDP-43/FUS toward pathology. Your hypothesis fits current evidence best when framed as:
If you want, I’ll sketch the exact imaging/analysis pipeline (markers, timepoints, FRAP settings, stats) so it’s plug-and-play for an iPSC MN experiment.
