Understanding Stathmin-2’s Impact on ALS Motor and Sensory Denervation: Cathleen M. Lutz, PhD

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The vice president of the Rare Disease Translational Center at the Jackson Laboratory discussed results from a recently published study reinforcing stathmin-2 as a potential therapeutic strategy for ALS. [WATCH TIME: 4 minutes]

WATCH TIME: 4 minutes

"We are seeing signs that transient depletion of stathmin-2 will provide you with over time, not immediately, what we would see as a progressive, sensory neuropathy and also a motor neuropathy."

Part of the reason for the lack of drug development in amyotrophic lateral sclerosis (ALS) has been because of the limited, validated biomarkers that correlate with disease progression. Tofersen (Qalsody; Biogen), the first FDA-approved therapy for SOD1-mutated ALS, had its approval based on changes in neurofilament light (Nfl), a surrogate biomarker of neuroaxonal damage, even while showing no significant difference vs placebo on ALS Functional Rating Scale, a common measure in ALS trials.

Recent research has discovered that a mislocalization of the RNA-binding protein TAR DNA-binding protein 43 (TDP-43) in affected neurons is found in nearly all patients with ALS and about half of patients with frontotemporal dementia (FTD).1 Aside from TDP-43 aggregation, nuclear clearance of TDP-43 is observed in affected neurons in sporadic ALS and FTD and in the most frequent genetic cause of ALS and FTD, a GGGGCC repeat expansion in the C9orf72 gene.

A paper published in October 2023 showed that stathmin-2 has an important role in the establishment and maintenance of neurofilament-dependent axoplasmic organization that is critical for preserving the caliber and conduction velocity of myelinated large-diameter axons.2 Cathleen M. Lutz, PhD, an investigator on the study, recently sat down with NeurologyLive® to provide an overview of the data, and the significance it holds for the ALS community. Lutz, vice president of the Rare Disease Translational Center at the Jackson Laboratory, went into detail about the methods used in the study, including transient antisense oligonucleotide-mediated suppression, sustained shRNA-induced depletion in aging mice, and germline deletion.

REFERENCES
1. Arai, T. et al. TDP-43 is a component of ubiquitin-positive tau-negative inclusions in frontotemporal lobar degeneration and amyotrophic lateral sclerosis. Biochem. Biophys. Res. Commun. 351, 602–611 (2006).
2. 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
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