ALS IMPLICATED PROTEIN TDP-43 SUSTAINS LEVELS OF STMN2 A MEDIATOR OF MOTOR NEURON GROWTH AND REPAIR

Nat Neurosci, 2019 · DOI: 10.1038/s41593-018-0300-4 · Published: February 1, 2019

Regenerative Medicine Neurology Genetics

Simple Explanation

This study investigates the role of TDP-43, a protein linked to Amyotrophic Lateral Sclerosis (ALS), in regulating RNA metabolism in motor neurons. The researchers found that TDP-43 affects the expression of STMN2, a gene crucial for motor neuron growth and repair. Restoring STMN2 expression could potentially be a therapeutic strategy for ALS.

Study Duration

Not specified

Participants

Post-mortem samples from 3 sporadic ALS cases and 3 controls

Evidence Level

Not specified

Key Findings

1
TDP-43 knockdown in human motor neurons (hMNs) leads to decreased STMN2 expression due to altered splicing.
2
STMN2 is necessary for normal axonal outgrowth and regeneration in hMNs.
3
Post-translational stabilization of STMN2, achieved through JNK inhibition, rescues neurite outgrowth and axon regeneration deficits induced by TDP-43 depletion.

Research Summary

The study identifies RNAs regulated by TDP-43 in human motor neurons, revealing that STMN2 expression declines after TDP-43 knockdown and mislocalization. It demonstrates that STMN2 is essential for axonal outgrowth and regeneration, and its depletion resulting from loss of TDP-43 activity is relevant to people with ALS. The research suggests restoring STMN2 expression as a potential therapeutic approach for ALS, supported by the finding that JNK inhibition rescues STMN2 levels and neurite defects.

Practical Implications

Therapeutic Target

Restoring STMN2 expression could be a potential therapeutic strategy for ALS.

Drug Development

JNK inhibitors may be further explored to rescue STMN2 levels in ALS.

Disease Modeling

The study highlights the value of human cellular disease models.

Study Limitations

1
The study primarily uses in vitro models.
2
The precise mechanisms of TDP-43 mislocalization.
3
Further studies with iPS cell-derived neurons from FUS and C9ORF72 patients could shed light on these hypotheses.

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