PT  - JOURNAL ARTICLE
AU  - Katarina Stoklund Dittlau
AU  - Emily N. Krasnow
AU  - Laura Fumagalli
AU  - Tijs Vandoorne
AU  - Pieter Baatsen
AU  - Axelle Kerstens
AU  - Giorgia Giacomazzi
AU  - Benjamin Pavie
AU  - Maurilio Sampaolesi
AU  - Philip Van Damme
AU  - Ludo Van Den Bosch
TI  - Human motor units in microfluidic devices are impaired by FUS mutations and improved by HDAC6 inhibition
AID  - 10.1101/2020.10.21.346874
DP  - 2020 Jan 01
TA  - bioRxiv
PG  - 2020.10.21.346874
4099  - http://biorxiv.org/content/early/2020/10/21/2020.10.21.346874.short
4100  - http://biorxiv.org/content/early/2020/10/21/2020.10.21.346874.full
AB  - Neuromuscular junctions (NMJs) ensure proper communication between motor neurons and muscle through the release of neurotransmitters. In motor neuron disorders, such as amyotrophic lateral sclerosis (ALS), NMJs degenerate resulting in muscle atrophy, paralysis and respiratory failure. The aim of this study was to establish a versatile and reproducible in vitro model of a human motor unit to study the effect of ALS-causing mutations. Therefore, we generated a co-culture of human induced pluripotent stem cell-derived motor neurons and human primary mesoangioblast-derived myotubes in microfluidic devices. A chemotactic and volumetric gradient facilitated the growth of motor neuron neurites through microgrooves resulting in the interaction with myotubes and the formation of NMJs. We observed that ALS-causing FUS mutations resulted in a reduced neurite outgrowth and in a decreased NMJ number. Interestingly, the selective HDAC6 inhibitor, Tubastatin A, improved the neurite outgrowth and the NMJ morphology of FUS-ALS co-cultures, further prompting HDAC6 inhibition as a potential therapeutic strategy for ALS.Competing Interest StatementThe authors have declared no competing interest.