ALS-related p97 R155H mutation disrupts lysophagy in iPSC-derived motor neurons

Klickstein, Jacob A.; Johnson, Michelle A.; Antonoudiou, Pantelis; Maguire, Jamie; Paulo, Joao A.; Gygi, Steve P.; Weihl, Chris; Raman, Malavika

doi:10.1016/j.stemcr.2024.01.002

Stem Cell Reports

2024

DOI: 10.1016/j.stemcr.2024.01.002

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ALS-related p97 R155H mutation disrupts lysophagy in iPSC-derived motor neurons

Jacob A. Klickstein,

Michelle A. Johnson,

Pantelis Antonoudiou

et al.

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2024

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Cited by 3 publications

References 73 publications

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Autophagy, aging, and age-related neurodegeneration

Palmer,

Wilson,

Son

et al. 2024

Neuron

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Autophagy, aging, and age-related neurodegeneration

Palmer,

Wilson,

Son

et al. 2024

Neuron

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Ubiquitin regulatory X (UBX) domain-containing protein 6 is essential for autophagy induction and inflammation control in macrophages

Kim,

Lee,

Park

et al. 2024

Cell Mol Immunol

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Ubiquitin regulatory X (UBX) domain-containing protein 6 (UBXN6) is an essential cofactor for the activity of the valosin-containing protein p97, an adenosine triphosphatase associated with diverse cellular activities. Nonetheless, its role in cells of the innate immune system remains largely unexplored. In this study, we report that UBXN6 is upregulated in humans with sepsis and may serve as a pivotal regulator of inflammatory responses via the activation of autophagy. Notably, the upregulation of UBXN6 in sepsis patients was negatively correlated with inflammatory gene profiles but positively correlated with the expression of Forkhead box O3, an autophagy-driving transcription factor. Compared with those of control mice, the macrophages of mice subjected to myeloid cell-specific UBXN6 depletion exhibited exacerbated inflammation, increased mitochondrial oxidative stress, and greater impairment of autophagy and endoplasmic reticulum-associated degradation pathways. UBXN6-deficient macrophages also exhibited immunometabolic remodeling, characterized by a shift to aerobic glycolysis and elevated levels of branched-chain amino acids. These metabolic shifts amplify mammalian target of rapamycin pathway signaling, in turn reducing the nuclear translocation of the transcription factor EB and impairing lysosomal biogenesis. Together, these data reveal that UBXN6 serves as an activator of autophagy and regulates inflammation to maintain immune system suppression during human sepsis.

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Elevated VCP ATPase Activity Correlates With Disease Onset in Multisystem Proteinopathy-1

Robinson,

Findlay,

et al. 2024

Neurol Genet

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ObjectivesMultisystem proteinopathy-1 (MSP1) is a late onset disease with >50 pathogenic variants in p97/VCP. MSP1 patients have multiple phenotypes that include inclusion body myopathy, Paget disease of the bone, amyotrophic lateral sclerosis, and frontotemporal dementia. There have been no clear genotype-phenotype correlations. We sought to identify genotype-phenotype correlations and associate these with VCP intrinsic ATPase activity.MethodsPatients with MSP1 were identified from the literature and the Cure VCP patient registry. Age at onset and at loss of ambulation were collated. VCP intrinsic ATPase activity was evaluated from recombinant purified protein.ResultsAmong the 5 most common pathogenic VCP variants in MSP1 patients, R155C patients had the earliest average age at onset (38.15 ± 9.78). This correlated with higher ATPase activity. Evaluation of 5 variants confirmed an inverse correlation between age at onset and ATPase activity (r = −0.94, p = 0.01).DiscussionPrevious studies have reported that VCP pathogenic variants are “hyperactive.” Whether this elevation in VCP ATPase activity is relevant to disease is unclear. Our study supports that in vitro VCP activity correlates with disease onset and may guide the prognosis of patients with rare or unreported variants. Moreover, it suggests that inhibition of VCP ATPase activity in MSP1 may be therapeutic.

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ALS-related p97 R155H mutation disrupts lysophagy in iPSC-derived motor neurons

Cited by 3 publications

References 73 publications

Autophagy, aging, and age-related neurodegeneration

Autophagy, aging, and age-related neurodegeneration

Ubiquitin regulatory X (UBX) domain-containing protein 6 is essential for autophagy induction and inflammation control in macrophages

Elevated VCP ATPase Activity Correlates With Disease Onset in Multisystem Proteinopathy-1

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