Disrupted mannosidase enzymes in C9orf72 ALS/FTD

Ondatje, B. N.; Gittings, L. M.; Preller, K. R.; Alsop, E.; Garcia-Mansfield, K.; Hansen, N.; Lovell, B.; Sharma, R.; Piras, I. S.; Martinez, M.; Meechoovet, B.; Bonfitto, A.; Song, S.; Levy, J.; Huentelman, M.; Pirrotte, P.; Van Keuren-Jensen, K.; Sattler, R.

doi:10.64898/2026.10.30.763135

bioRxiv · 10.64898/2026.10.30.763135

Disrupted mannosidase enzymes in C9orf72 ALS/FTD

Ondatje, B. N.·Gittings, L. M.·Preller, K. R.·Alsop, E.·Garcia-Mansfield, K.·Hansen, N.·Lovell, B.·Sharma, R.·Piras, I. S.·Martinez, M.·Meechoovet, B.·Bonfitto, A.·Song, S.·Levy, J.·Huentelman, M.·Pirrotte, P.·Van Keuren-Jensen, K.·Sattler, R.

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Abstract

Amyotrophic lateral sclerosis (ALS) is an age-related neurodegenerative disorder resulting from the loss of motor neurons in the brain and spinal cord. Neuroinflammation, induced by glial cells including microglia (MG) and astrocytes, is an acknowledged aspect of this neurodegeneration. Generating induced pluripotent stem cell (iPSC) neuroinflammatory models of ALS may help elucidate non-neuronal mechanisms of disease. Here, we analyze human postmortem tissue and an iPSC derived glia-crosstalk model identifying a reduction in Golgi enzymes MAN1A1 and MAN1A2 in addition to other glycan enzymes from ALS-associated microglia and astrocytes. Impaired Golgi and glycan metabolism is linked to inflammation and other related ALS disease mechanisms including impaired lysosomal proteostasis, altered extracellular matrix, disrupted secretion, and altered cell-cell signaling.

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Ondatje, B. N., Gittings, L. M., Preller, K. R., Alsop, E., Garcia-Mansfield, K., Hansen, N., Lovell, B., Sharma, R., Piras, I. S., Martinez, M., Meechoovet, B., Bonfitto, A., Song, S., Levy, J., Huentelman, M., Pirrotte, P., Van Keuren-Jensen, K., Sattler, R.. 2026-11-04. Disrupted mannosidase enzymes in C9orf72 ALS/FTD. https://doi.org/10.64898/2026.10.30.763135

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