New study on neuropathies upon loss of TDP43-regulated RNA Stmn2
Irune Guerra San Juan (FGA) & team show neuropathies may develop in ALS patients when a poison exon in Stmn2 mRNA is not excised due to TDP43 dysfunction. The study is a collaboration with Harvard University published in Neuron on March 15th
Amyotrophic lateral sclerosis (ALS) is characterized by fatal motor decline accompanied by pathological aggregation and loss of function of the RNA-binding protein TDP43 in degenerating motor neurons. When TDP-43 accumulates in the cytoplasm, its levels decline in the nucleus and many of the RNAs that it normally regulates are altered in their splicing and overall expression. Previous work from the Eggan and Cleveland labs found STMN2, one of the most abundant transcripts in motor neurons, to be tightly regulated by TDP-43, and its expression to be reduced in a subset of ALS patients. Thus far, it remains unresolved to what extent the loss of normal regulation of TDP-43 client-RNAs that occurs in ALS meaningfully contributes to motor system dysfunction. In this study, Irune Guerra San Juan, Leslie Nash and colleagues employed gene editing to find whether the mouse ortholog of STMN2 is involved in maintaining the motor system. Both mosaic founders and homozygous loss-of-function Stmn2 mice exhibited age-dependent neuromuscular junction denervation and fragmentation, resulting in muscle atrophy and impaired motor behavior, accompanied by an imbalance in neuronal microtubule dynamics in the spinal cord. The introduction of human STMN2 through BAC transgenesis was sufficient to rescue the motor phenotypes observed in Stmn2 mutant mice.
Together, the findings demonstrate that disrupting the ortholog of a single TDP43-regulated RNA is sufficient to cause substantial motor dysfunction. The absence of a variety of ALS phenomenon (motor neuron loss, glial activation and TDP-43 pathology) that do not occur in Stmn2 mutant mice is instructive as they may provide some clarity on where alterations in STMN2 may reside on the pathway to motor neuron degeneration in ALS. Ultimately, these results support the notion that restoration of STMN2 expression in patients who exhibit TDP43 pathology may provide a meaningful therapeutic strategy to improve motor axon function.
The study was published online in the March 15th issue of Neuron