Neuronal genetic rescue normalizes brain network dynamics in a lysosomal storage disorder despite persistent storage...

Area of Science:

• Neuroscience
• Genetics
• Biochemistry

Background:

• Lysosomal storage disorders (LSDs) often cause neurologic symptoms, but mechanisms of brain dysfunction remain unclear.
• A key question is whether storage accumulation directly causes defects or is a bystander.
• The impact of cell-type-specific gene loss in LSDs is largely unknown.

Purpose of the Study:

• To investigate the impact of cell-type-specific genetic rescue on neural circuit dysfunction in CLN3 disease.
• To determine if neuronal or astrocytic Cln3 restoration corrects network abnormalities.
• To clarify the role of storage accumulation versus neuronal dysfunction in CLN3 disease pathogenesis.

Main Methods:

• Utilized a CLN3 disease mouse model.
• Employed AAV-mediated gene delivery for Cln3 expression restoration.
• Performed conditional genetic rescue in specific cell types (neurons and astrocytes).
• Assessed electrophysiologic markers of neural network function.

Main Results:

• Low-level Cln3 expression rescue specifically in neurons normalized electrophysiologic markers of network dysfunction.
• Neuronal rescue was effective despite persistent histopathology and storage.
• Restoring Cln3 expression in astrocytes did not normalize network function.

Conclusions:

• Loss of CLN3 function in neurons, not storage accumulation, is the primary driver of neurologic dysfunction in CLN3 disease.
• Targeting neuronal Cln3 restoration is a promising therapeutic strategy.
• Storage clearance may not be an effective therapeutic target or biomarker for CLN3 disease.