Moving forward in clinical trials for ALS: motor neurons lead the way please

Abstract

Amyotrophic lateral sclerosis (ALS) is one of the most complex motor neuron diseases. Even though scientific discoveries are accelerating with an unprecedented pace, to date more than 30 clinical trials have ended with failure and staggering frustration. There are too many compounds that increase life span in mice, but too little evidence that they will improve human condition. Increasing the chances of success for future clinical trials requires advancement of preclinical tests. Recent developments, which enable the visualization of diseased motor neurons, have the potential to bring novel insight. As we change our focus from mice to motor neurons, it is possible to foster a new vision that translates into effective and long-term treatment strategies in ALS and related motor neuron disorders (MND).

FIGURE 1

eGFP expression under the control of ubiquitin C-terminal hydrolase-L1 (UCHL1) promoter selectively labels corticospinal motor neurons (CSMN) in UCHL1-eGFP mice [37]. CSMN are large pyramidal neurons that are located in layer V of the motor cortex. They are subcerebral projection neurons and the corticospinal tract passes through the pons and enters the spinal cord at the pyramidal decussation, traveling at the dorsal funiculus of the spinal cord until it reaches spinal targets.

FIGURE 2

The ubiquitin C-terminal hydrolase-L1 (UCHL1)-eGFP reporter mouse model provides an invaluable tool to study motor neuron degeneration in animal models of amyotrophic lateral sclerosis and related motor neuron disorders (ALS/MND). Upon proper mating strategies, ALS/MND mouse models with eGFP+ corticospinal motor neurons (CSMN) can be generated. In these transgenic disease models, vulnerable CSMN are genetically labeled in the motor cortex (green triangle) and can be visually identified among others that are not genetically labeled (gray triangle). In the spinal cord of UCHL1-eGFP mice, the eGFP expression becomes restricted to small-diameter spinal motor neurons (SMN) at P30 and genetically labels SMN that are mostly resistant to degeneration (green stars). Abbreviation: ChAT, Choline acetyl transferase.

FIGURE 3

The ubiquitin C-terminal hydrolase-L1 (UCHL1)-eGFP reporter mouse enables investigation of neuroprotection provided to vulnerable and diseased corticospinal motor neurons (CSMN) by compound and/or drug treatment. The compounds can be administered orally by drinking water or food. Alternatively, they can be directly delivered by intraperitoneal injection. CSMN survival can be monitored and quantitatively analyzed at different stages of the disease, together with other measures for improved motor function (e.g. Grip test or gait analysis). Spinal motor neuron (SMN) neuroprotection can still be studied using conventional methods such as Nissl histology or ChAT immunofluorescence, with the added benefit of visualizing and assessing the numbers of degeneration-resistant SMN separately, distinguished by eGFP expression.