Modulating membrane fluidity corrects Batten disease phenotypes in vitro and in vivo

Area of Science:

• Neuroscience
• Genetics
• Cell Biology

Background:

• Neuronal ceroid lipofuscinoses (NCLs) are inherited neurodegenerative diseases.
• The most common form, juvenile CLN3 disease, results from CLN3 gene mutations.
• CLN3 protein loss impacts cellular processes, including blood-brain barrier (BBB) function.

Purpose of the Study:

• To investigate the effects of CLN3 deficiency on BBB components.
• To evaluate the therapeutic potential of carbenoxolone (CBX) and other small molecules in CLN3 deficiency models.

Main Methods:

• Utilized Cln3-deficient mouse models and patient-derived cell studies.
• Assessed BBB permeability, astrocyte endfeet morphology, and endothelial cell functions.
• Employed carbenoxolone (CBX) treatment and screened compounds via the NIH LINCS program.

Main Results:

• Cln3 deficiency increased astrocyte endfeet area and BBB permeability.
• CBX treatment corrected BBB defects, normalized lipid microdomains, and improved endothelial cell functions (endocytosis, caveolin-1 distribution, Cdc42 activity).
• CBX and LINCS-identified compounds reduced autofluorescence and improved BBB responses in Cln3-deficient mice.

Conclusions:

• CLN3 deficiency disrupts BBB integrity and astrocyte morphology.
• Carbenoxolone (CBX) effectively ameliorates cellular and BBB defects associated with CLN3 deficiency.
• CBX and other identified compounds show therapeutic promise for CLN3 deficiency, potentially through novel mechanisms.