Disrupted mannosidase enzymes in C9orf72 ALS/FTD

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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Publication Details

Journal
bioRxiv (Cold Spring Harbor Laboratory)
Published
2026-11-04
DOI
https://doi.org/10.64898/2026.10.30.763135
Primary Topic
Amyotrophic Lateral Sclerosis Research
Type
preprint
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preprint

Disrupted mannosidase enzymes in C9orf72 ALS/FTD

Anna Bonfitto, Bessie Meechoovet, Briana N. Ondatje, Kendall R. Van Keuren‐Jensen et al.
bioRxiv (Cold Spring Harbor Laboratory)
Amyotrophic Lateral Sclerosis Research
preprint

Disrupted mannosidase enzymes in C9orf72 ALS/FTD

Anna Bonfitto, Bessie Meechoovet, Briana N. Ondatje, Kendall R. Van Keuren‐Jensen, Eric B. Alsop, Matthew J. Huentelman, Lauren M. Gittings, Nate Hansen, Ritin Sharma, Serena Song, Krystine Garcia‐Mansfield, Patrick Pirrotte, Ignazio Stefano Piras, Rita Sattler, Melissa Martínez, Brooke Lovell, Jennifer R. Levy, Kim R Preller
preprint en

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.

bioRxiv (Cold Spring Harbor Laboratory)
Translational Genomics Research Institute (US), Barrow Neurological Institute (US)
Amyotrophic Lateral Sclerosis Research
DOISourceOpenAlex
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