Steps to Validate Stathmin-2 as an ALS-Specific Biomarker: Cathleen Lutz, PhD

WATCH TIME: 3 minutes

"Certainly, in the face of TDP-43 nuclear loss, we see many changes in RNA splicing and the transcriptome. The ongoing question is whether stathmin-2 restoration, such as with antisense oligonucleotide therapy, will be enough to influence the disease. Will other cellular components need modification? It's an ongoing question, but we're moving in the right direction."

In both familial and sporadic forms of amyotrophic lateral sclerosis (ALS), the loss of neuromuscular junctions (NMJs) has been established as one of the earliest pathological events. NMJs are vital synapses formed between motor neuron terminals and muscle cells, and their disruption occurs before disease onset and motor neuron degeneration in ALS. Several efforts focused on maintaining motor neuron survival have failed to prevent muscle denervation or delay disease onset, suggesting that pathological mechanisms involved in muscle denervation occur independently from the death of the motor neuron.

Recently published in Nature, a group of investigators evaluated stathmin-2 protein, a protein that is reduced in the spinal cord of most patients with ALS. In the analysis, Cathleen M. Lutz, PhD, and colleagues used a combination of approaches, including transient antisense oligonucleotide-mediated suppression, sustained shRNA-induced depletion in aging mice, and germline deletion. Results demonstrated that not only does stathmin-2 accumulate at the axon terminals of mature motor and sensory neurons in the adult nervous system, but also that there is a continuing requirement for stathmin-2 in the maintenance of motor and sensory neuron synapses.

Additional results showed that reduction in stathmin-2 did not compromise motor neuron survival in mice during the 8-month period observed, suggesting that these effects may take longer to see. Lutz, vice president of the Rare Disease Translational Center at the Jackson Laboratory, recently sat down with NeurologyLive^® to discuss the next steps following this research and the need to further validate stathmin-2 as an ALS-specific disease-modifying biomarker.

REFERENCE
1. Lopez-Erauskin J, Bravo-Hernandez M, Presa M, et al. Stathmin-2 loss leads to neurofilament-dependent axonal collapse driving motor and sensory denervation. Nature. Published online November 23, 2023. doi:10.1038/s41593-023-01496-0