Tubulin associated stathmin-2 has a critical role in the maintenance of the adult motor neuron system


Translational Research

Poster Number: 44


Jone Lopez Erauskin PhD


1. Ludwig Institute For Cancer Research. UCSD

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease in which premature loss of upper and lower motor neurons leads to fatal paralysis. A landmark contribution to understanding cellular mechanisms of ALS came from the discovery of cytoplasmic accumulation and nuclear loss of the RNA binding protein TDP-43 from affected neurons in most instances of ALS (>95%).
TDP-43 disruption represents a common pathological hallmark in both sporadic and familial forms of ALS including patients with mutations in the genes encoding for TDP-43 (TARDBP).
The loss of neuron-specific tubulin-associated protein stathmin-2 has recently been identified as a major alteration linked to TDP-43 loss of nuclear function. The relevant role of stathmin-2 in the development of the nervous system and the axonal regeneration after injury is widely recognized, however, whether it places any role in an adult nervous system is currently unknown.
Using different approaches to deplete murine stathmin-2 in an otherwise normal mouse adult nervous system has unraveled stathmin-2 as a crucial component for motor neuron maintenance. Sustained reduction of stathmin-2 in spinal cords of adult wild-type mice by intraventricular delivery of antisense oligonucleotides or subpial delivery of AAV9 encoding an shRNA against murine stathmin-2 resulted in progressive hindlimb motor deficits, reduction on nerve conduction velocity, and muscle denervation.
Our work uncovers the functional importance of stathmin-2 in the adult nervous system to preserve the neuronal function of motor neurons and most importantly reinforces the restoration of stathmin-2 as a critical therapeutic approach for TDP-43-dependent neurodegenerative diseases.