ALS mutations do not alter perineuronal net formation in human stem cell-derived motor neurons

Area of Science:

• Neuroscience
• Cell Biology
• Extracellular Matrix Biology

Background:

• Perineuronal nets (PNNs) stabilize synapses and regulate neuronal plasticity.
• PNN dysregulation is implicated in neurological disorders, but its role in amyotrophic lateral sclerosis (ALS) is not fully understood.
• The cell-intrinsic contribution of motor neurons (MNs) to PNN alterations in ALS is unknown.

Purpose of the Study:

• To investigate PNN formation in human induced pluripotent stem cell (iPSC)-derived MNs in vitro.
• To determine if ALS-associated mutations affect PNN formation in iPSC-derived MNs.
• To explore the cellular basis of PNN dysregulation in ALS.

Main Methods:

• Co-culture of iPSC-derived MNs and astrocytes to form PNN-like structures.
• Analysis of PNN formation and gene expression in the presence of ALS mutations.
• Meta-analysis of transcriptomic datasets from iPSC-derived astrocytes and MN populations.
• Transcriptomic analysis of human post-mortem ALS tissues.

Main Results:

• PNN-like structures containing hyaluronan, tenascin-R, and aggrecan formed in vitro.
• ALS mutations did not alter PNN formation or gene expression in iPSC-derived MNs.
• No consistent PNN-related gene expression differences were found in iPSC-derived MNs.
• Transcriptomic analysis of post-mortem ALS tissues revealed PNN gene dysregulation.

Conclusions:

• ALS-associated mutations in MNs alone do not reproduce PNN alterations observed in animal models.
• PNN dysregulation in ALS likely involves contributions from other central nervous system cell types.
• Findings suggest a broader cellular context for PNN involvement in ALS pathogenesis.