The effect of mind-linked gene disruption in GLIA

Abstract

Amyotrophic lateral sclerosis (ALS) and spinal muscular atrophy (SMA) are the most common motor neuron diseases (MNDs) in adults and infants respectively. Both ALS and SMA are characterised by motor neuron loss, muscle atrophy, loss of movement and respiratory insufficiency, which most commonly leads to mortality. Multiple genes are involved in ALS pathogenesis including C9orf72, TARDBP/TDP-43, and FUS. Pathogenic mechanisms involve both loss and gain of function including aberrant messenger RNA (mRNA) processing and trafficking, and production of cytoplasmic inclusions including C9orf72-associated dipeptide repeat aggregates. SMA pathology revolves around the SMN gene where its deletion leads to a decreased SMN protein concentration. SMN together with Gemins 2-8, Unrip, pICln and Tgs1 are required to produce small nuclear ribonucleoproteins (snRNPs), essential for mRNA splicing. Glial involvement in MND has been a subject of current research. The main glial cells are astrocytes, oligodendrocytes, and microglia, fundamental for motor neuron health and maintenance. Using Drosophila melanogaster as a model organism and the bipartite GAL4- UAS system, various ALS- and SMA-linked genes were disrupted selectively in glia and flies were assessed for motoric ability and survival. Disruption of the ALS-linked TDP-43, FUS, C9orf72 and SCFD1 led to significant decreases in larval mobility with the large majority of all transgenes applied inducing complete loss of adult fly viability. Disruption of the SMA-linked SMN, pICln, Tgs1 and Gemin3 did not affect larval mobility with the exception of Gemin8/Valette. Nonetheless, viability was negatively affected on disruption of nearly all SMA-linked genes. These results show a very important glial contribution to the normal pathogenesis of MND and uncover novel contributors to the function and survival of glia. This can be exploited for future therapeutic strategies possibly enhancing their effectiveness.