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Early-onset neuroinflammation drives neurodegeneration caused by lysosomal PI(3,5)P2 insufficiency

Bridget Wong1, Morgan Payne2, Alexander Silva3

  • 1Department of Pathology, University of California San Diego, San Diego, CA 92093, USA.

Neurobiology of Disease
|June 4, 2026
PubMed

Insights

Phosphatidylinositol 3,5-bisphosphate [PI(3,5)P2] deficiency causes fatal neurological diseases. Early neuroinflammation, including microglial activation and cell death pathways, precedes neurodegeneration, implicating lysosomal dysfunction in brain development and disease.

Area of Science:

  • Neuroscience
  • Molecular Biology
  • Genetics

Background:

  • Phosphatidylinositol 3,5-bisphosphate [PI(3,5)P2] is a critical lysosomal lipid.
  • Deficiency in PI(3,5)P2, due to mutations in PIKfyve complex genes (e.g., Fig. 4, VAC14), underlies severe neurological disorders like Charcot-Marie-Tooth type 4J (CMT4J) and amyotrophic lateral sclerosis (ALS).
  • Understanding the brain's molecular response to PI(3,5)P2 insufficiency is crucial for deciphering these diseases.

Purpose of the Study:

  • To comprehensively map the molecular consequences of PI(3,5)P2 insufficiency in the brain.
  • To investigate the role of lysosomal function in neurodevelopment and neuroinflammation.
  • To identify key molecular players and pathways involved in PI(3,5)P2-deficiency-driven neurodegeneration.

Main Methods:

  • Quantitative proteomic and transcriptomic analyses were performed on three mouse models with loss-of-function mutations in Fig. 4 or Vac14.
  • Brain tissues were examined at both presymptomatic (postnatal day 5) and end stages.
  • Isolated microglia were analyzed for their transcriptional state and reactive oxygen species production.

Main Results:

  • Profound neuroinflammation, characterized by complement activation, interferon signaling, and myeloid/T-cell infiltration, was evident by postnatal day 5, preceding significant neurodegeneration.
  • Mutant microglia displayed a pro-oxidative transcriptional state, indicating a non-cell-autonomous phenotype.
  • PI(3,5)P2 insufficiency disrupted the normal developmental remodeling of the brain proteome, with key proteins failing to accumulate during postnatal maturation.
  • Multifactorial inflammatory cell death pathways (apoptosis, pyroptosis, necroptosis) were activated, involving elevated levels of p53, Fas receptor, inflammatory caspases, Gasdermin D, RIPK1, and ZBP1.
  • Dysregulated proteins were linked to genes implicated in lysosomal storage disorders and neurodegenerative diseases (ALS, CMT, Alzheimer's, Parkinson's).

Conclusions:

  • Early-onset neuroinflammation is a defining and likely initiating feature of neurodegeneration caused by lysosomal PI(3,5)P2 disruption.
  • Lysosomal function is critical for proper neurodevelopment and brain proteome maturation.
  • The findings highlight the broad pathogenic relevance of PI(3,5)P2 insufficiency across a spectrum of neurological and lysosomal storage disorders.
Keywords:
AstrocyteFasFig4LysosomeMicrogliaNeuroinflammationPI(3,5)P2PIKfyvePhosphoinositideReactive oxygen speciesVac14cGAS-STINGp53

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