ALS program

Aiming for "a world that can treat ALS", our drug discovery business is also an important mission.

The NMJ is a target of our drug discovery

The concept of our company -The normal condition and the function failure of NMJ

Skeletal muscle is the largest organ in our body and plays an essential role in our every movement. However, muscle itself is not sufficient for us to regulate its contraction. For our ability to control muscle, the motor neuron terminal should be connected to the muscle and release a neurotransmitter called acetylcholine. The tissue structure connecting the motor nerve terminal and skeletal muscle is the neuromuscular junction (NMJ). The NMJ is essential for our abilities to move, stand, speak, eat and breathe. Thus, it is critical for us to develop and maintain robust NMJ in order to live a healthy life.

Amyotrophic lateral sclerosis (ALS) is a devastating and lethal rare disease which causes gradual loss of motor function, leading to the respiratory failure at the end, while perceptions and brain functions remain intact. In only about 17% of the patients there is a family history of the condition, but there is no cure for them; for more than 80% of cases the causes have yet to be identified (this is called sporadic ALS). This fact makes it difficult for us to discover new therapies for ALS. It is known that motor neurons somehow die in the patients; this happens in the late stage, but not in the early stage, of the disease. On the other hand, both of familial and sporadic ALS patients show pathology at the NMJ, which is the first pathological symptom for the patients. In their tissue, the motor nerve terminal is detached from the muscle, suggesting that the muscle is no longer under the control of the motor neuron. This is sufficient for muscle paralysis and matches the fact that many ALS patients experience muscle paralysis in the early stage of the disease.

Our company believes that it is very important to understand what causes detachment of the motor nerve terminal from muscle in order to identify the fundamental causes of the disease. In addition, strengthening and promoting the connection between the motor nerve terminal and the muscle at the NMJ will lead us to novel therapeutics for ALS. This is our company’s concept and we are doing our best to discover the breakthrough for ALS targeting the NMJ.

Schaefer. et. al. J Comp Neurol. 2005 Sep 26;490(3):209-19. Image of immunostaining of the muscle tissue from the ALS model mouse. At the healthy site, the motor axon (green) is connected to the receptor cluster in muscle (red), generating the NMJ (A3, yellow). In contrast, at many pathological sites, the motor nerve terminal is detached from the muscle (A1 and A2).

How is the NMJ formed and maintained?

The NMJ is formed in fetal individuals in the womb during development and is maintained throughout life. Reciprocal exchanges of signals between motor neurons and skeletal muscle are necessary to create the normal NMJ. It has been known that a receptor tyrosine kinase called MuSK (Muscle Specific Kinase) and a glycoprotein called Agrin play critical roles for the interactions. In addition, it was recently found that a membrane protein in muscle, Lrp4 (Low-density lipoprotein receptor-related protein 4), functions retrogradely toward the motor nerve terminal and induces neuromuscular synapse formation (ref. 2). Figure 2 shows that purified Lrp4 proteins directly induce formation of the neurotransmitter releasing sites, indicating that Lrp4 plays a critical role in initiating the interaction between the motor nerve terminal and skeletal muscle. Furthermore, it has been shown that Lrp4 is important in maintaining the NMJ during adulthood as well (ref. 3). Taken together, the role of Lrp4 to form as well as to maintain the functional NMJ is direct and essential.

The NMJ is a target of our drug discovery

We have described that Lrp4 is necessary to form and to maintain the functional NMJ. This suggests that the malfunction of Lrp4 could directly and/or indirectly contribute to the dysfunction of the NMJ. This, in contrast, indicates that strengthening and promoting the Lrp4 function would lead to enhancing the NMJ function. This drives us to investigate further the mechanisms of NMJ formation, maintenance, and pathology with the ultimate target of identifying new drugs for the treatment of ALS.

We focus on the activity of Lrp4 toward motor neurons and by mimicking NMJ formation in vitro with our technology we aim to find novel therapeutic targets and therapeutics for ALS, that would strengthen and/or promote NMJ formation.

Yumoto. et. al. Nature. 2012 Sep 20;489(7416):438-42. The effect of control proteins or purified Lrp4 on cultured motor neurons. The Synapsin signal (red) is uniformly distributed when the control proteins were added to the cultured motor neurons (green) (left column). Synapsin was accumulated and the NMJ-like structure was formed when purified Lrp4 proteins were added to the motor neurons (right column).

References

1.Schaefer AM, Sanes JR, Lichtman JW. A compensatory subpopulation of motor neurons in a mouse model of amyotrophic lateral sclerosis. J Comp Neurol. 2005 Sep 26;490(3):209-19
2.Yumoto N, Kim N, Burden SJ. Lrp4 is a retrograde signal for presynaptic differentiation at neuromuscular synapses. Nature. 2012 Sep 20;489(7416):438-42.
3.Barik A, Lu Y, Sathyamurthy A, Bowman A, Shen C, Li L, Xiong WC, Mei L. LRP4 is critical for neuromuscular junction maintenance. J Neurosci. 2014 Oct 15;34(42):13892-905.