TDP-43 Aggregation Leads to Loss of Stathmin-2 Expression and Inability of Neurons to Regenerate Axons

Researchers here delve into the mechanisms by which TDP-43 aggregation contributes to the symptoms of neurodegenerative conditions in which it is involved. It disrupts expression of another gene, stathmin-2, degrading the ability of neurons to maintain axonal connections. This is a feature of ALS, the condition most readily associated with TDP-43 aggregation. The research here points to an approach to therapy: not restoration of appropriate TDP-43 behavior, but rather finding a way to force correct expression of stathmin-2. It remains the case that TDP-43 aggregation may well cause other problems unrelated to this mechanism.

Nuclear clearance and cytoplasmic aggregation of the RNA-binding protein TDP-43 is the hallmark of neurodegenerative diseases called TDP-43 proteinopathies. This includes almost all instances of amyotrophic lateral sclerosis (ALS) and about half of frontotemporal dementia. In ALS, the motor neurons that innervate and trigger contraction of skeletal muscles degenerate, resulting in paralysis. One of the most highly abundant motor neuron mRNAs encodes stathmin-2, a protein necessary for axonal regeneration and maintenance of neuromuscular junctions (NMJs).

Recognizing that stathmin-2 is essential for axonal recovery after injury and NMJ maintenance, a central interest in TDP-43 proteinopathies is to determine the mechanism through which TDP-43 enables correct processing of STMN2 mRNAs and to develop methods to restore stathmin-2 synthesis in neurons with TDP-43 dysfunction. We found that TDP-43 binding to the first intron of the STMN2 pre-mRNA was required to suppress cryptic splicing and polyadenylation. Correct processing of this modified STMN2 pre-mRNA was restored by binding, suggesting that TDP-43 normally functions by sterically blocking access to the cryptic sites of RNA-processing factors.

Rescue of stathmin-2 expression and axonal regeneration after injury in human motor neurons depleted of TDP-43 was achieved with steric binding antisense oligonucleotides (ASOs). We identified RNA-targeted CRISPR effectors and ASOs that restored STMN2 levels despite reduced TDP-43. ASO injection into cerebral spinal fluid, an approach feasible for human therapy, rescued stathmin-2 protein levels in the central nervous system of mice with chronically misprocessed Stmn2 pre-mRNAs.


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