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PI3P: Rising to the (DPR) challenge in C9-ALS/FTD
Janani Parameswaran1, Zachary T McEachin2
1Department of Cell Biology, Emory University, Atlanta, GA 30322, USA.
Neuron
|May 8, 2025
Summary
A hexanucleotide repeat expansion in C9orf72 is linked to neurodegenerative diseases like ALS and FTD. Researchers found that increasing PI3P levels can reduce toxic protein buildup and neurotoxicity.
Area of Science:
- Neuroscience
- Genetics
- Cell Biology
Background:
- A hexanucleotide G4C2 repeat expansion in the C9orf72 gene is the primary genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD).
- This expansion leads to the production of dipeptide repeat (DPR) proteins, which accumulate and contribute to neurotoxicity.
- Endolysosomal pathway deficits are implicated in the pathogenesis of C9orf72-associated neurodegenerative diseases.
Purpose of the Study:
- To investigate the role of phosphoinositides, specifically phosphatidylinositol 3-phosphate (PI3P), in the cellular mechanisms underlying C9orf72-associated neurodegeneration.
- To determine if modulating PI3P levels can ameliorate the toxic effects of DPR proteins and endolysosomal dysfunction.
Main Methods:
- Utilized cellular and animal models of C9orf72 repeat expansion.
- Assessed endolysosomal trafficking and function.
- Quantified levels of dipeptide repeat proteins.
- Manipulated cellular PI3P levels through genetic or pharmacological approaches.
Main Results:
- Elevated PI3P levels were found to restore endolysosomal trafficking and function in models of C9orf72 disease.
- Increased PI3P significantly reduced the accumulation of toxic dipeptide repeat proteins.
- Mitigation of endolysosomal deficits and DPR accumulation correlated with reduced neurotoxicity.
Conclusions:
- Targeting PI3P metabolism represents a promising therapeutic strategy for C9orf72-associated ALS and FTD.
- Restoring endolysosomal homeostasis through PI3P modulation can counteract the neurotoxic effects of C9orf72 repeat expansions.
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