Stathmin-2 regulates microtubule dynamics and axonal resilience in human motor neurons

Amyotrophic lateral sclerosis (ALS) is characterized by the selective degeneration of motor neurons, but the mechanisms behind either causing neurodegeneration or providing neuronal resilience are not well understood. One key protein implicated in ALS is Stathmin-2 (STMN2), which is lost in nearly all cases and emerges as a central feature of the disease. However, the specific ways in which STMN2 maintains homeostasis in motor neurons are not fully defined.

In this study, researchers investigated the role of STMN2 in regulating the cytoskeleton and axonal function in human motor neurons. Using a technique called TIRF microscopy, they were able to observe STMN2-dependent changes in microtubule growth and "catastrophe" at a single-microtubule level. In human induced pluripotent stem cell-derived motor neurons, the researchers found that when STMN2 was depleted, there was an increased rate of microtubule polymerization - the process by which microtubules form.

However, the recovery of axonal microtubules after a brief treatment with nocodazole, which causes microtubules to depolymerize, was impaired in STMN2-depleted neurons. This suggests that STMN2 is necessary for efficient cytoskeletal remodeling after stress.

Further experiments revealed that STMN2-depleted neurons had a harder time recovering microtubules after acute depolymerization and exhibited reduced axonal "recoil" after optically induced local microtubule severing. Additionally, STMN2 depletion disrupted the formation of neuromuscular junction-like contacts in co-cultures of human motor neurons and muscle cells. These findings suggest that impaired cytoskeletal homeostasis, likely due to STMN2 loss, is linked to loss of distal neuronal connectivity.

Overall, this research identifies STMN2 as a crucial regulator of cytoskeletal resilience in motor neurons. The study shows that STMN2 coordinates microtubule remodeling, mitochondrial transport, and maintenance of neuromuscular junctions. The researchers propose that the inability of axonal cytoskeleton to remain resilient may be a critical point of vulnerability in motor neurons affected by ALS. Thus, cytoskeletal resilience could potentially be a therapeutic target downstream of TDP-43 pathology in ALS patients.