PhD student Irune Guerra San Juan from the Functional Genomics Lab at the Center for Neuroscience and Cognitive Research at VU Amsterdam shows 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 and is published in Neuron.

Amyotrophic lateral sclerosis (ALS) is a devastating condition characterized by fatal motor decline accompanied by pathological aggregation and loss of function of the RNA-binding protein TDP43 in degenerating motor neurons.

Loss of function of TDP43

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 colleagues at Harvard University 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.

Stmn2 deficiency

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.

Meaningful therapeutic strategy

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 phenomena (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.

Read the publication in Neuron: Loss of mouse Stmn2 function causes motor neuropathy

Source: Center for Neurogenomics and Cognitive Research