Lateral amyotrophic sclerosis-like onset after combined antiretroviral treatment initiation

Quevedo-Ramirez, Andres; Montenegro-Idrogo, Juan José; Resurrección-Delgado, Cristhian; Salazar-Mesones, Blanca; Gallardo-Cartagena, Jorge A; Cornejo-Venegas, Gonzalo; Méndez-Guerra, Carolina; Vargas-Matos, Iván; Chiappe-Gonzalez, Alfredo

doi:10.1016/j.idcr.2020.e00994

Cited by 4 publications

(2 citation statements)

References 11 publications

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“…Previous studies of HIV patients have shed further light on the relevance of the systemic immune system in ALS. These studies have reported a higher prevalence of ALS-like syndrome in HIV patients, which improves following anti-HIV treatment ( 79 – 83 ), correlating impaired immune system with ALS symptoms. Relative to the studies of motor neurons and glial cells in ALS, much less work has been done on the systemic aspect of ALS.…”

Section: Resultsmentioning

confidence: 99%

Causal ALS genes impact the MHC class II antigen presentation pathway

Chi,

Öztürk,

Paraggio

et al. 2023

Proc. Natl. Acad. Sci. U.S.A.

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Mutations in RNA/DNA-binding proteins cause amyotrophic lateral sclerosis (ALS), but the underlying disease mechanisms remain unclear. Here, we report that a set of ALS-associated proteins, namely FUS, EWSR1, TAF15, and MATR3, impact the expression of genes encoding the major histocompatibility complex II (MHC II) antigen presentation pathway. Both subunits of the MHC II heterodimer, HLA-DR, are down-regulated in ALS gene knockouts/knockdown in HeLa and human microglial cells, due to loss of the MHC II transcription factor CIITA. Importantly, hematopoietic progenitor cells (HPCs) derived from human embryonic stem cells bearing the FUS R495X mutation and HPCs derived from C9ORF72 ALS patient induced pluripotent stem cells also exhibit disrupted MHC II expression. Given that HPCs give rise to numerous immune cells, our data raise the possibility that loss of the MHC II pathway results in global failure of the immune system to protect motor neurons from damage that leads to ALS.

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Section: Resultsmentioning

confidence: 99%

Causal ALS genes impact the MHC class II antigen presentation pathway

Chi,

Öztürk,

Paraggio

et al. 2023

Proc. Natl. Acad. Sci. U.S.A.

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show abstract

“…Previous studies of HIV patients shed further light on the importance of the systemic immune system in ALS. These studies reported that HIV patients are more likely to exhibit an ALS-like syndrome, and this condition improves after anti-HIV treatment (Satin and Bayat 2021; Bowen et al 2016; MacGowan et al 2001; Quevedo-Ramirez et al 2020; Verma and Berger 2006). Relative to the studies of motor neurons and glial cells in ALS, much less work has been done on the systemic aspect of ALS.…”

Section: Resultsmentioning

confidence: 99%

Three ALS genes regulate expression of the MHC class II antigen presentation pathway

Chi

Öztürk

Paraggio

et al. 2022

Preprint

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Here we report that the major histocompatibility complex II (MHC II) antigen presentation pathway is regulated by the ALS-causative genes, FUS, TAF15, or MATR3. Of >6000 proteins detected by quantitative mass spectrometry, the subunits of the MHC II heterodimer, HLA-DR, were the top 2 downregulated proteins in HeLa knock outs (KO) of these ALS genes, but not the related gene, EWSR1. Moreover, CD74, which is the 3rd essential component of HLA-DR, was downregulated in the 3 KOs. We show that the downregulations are due to loss of CIITA, a transcription factor dedicated to expression of MHC II genes. Thus, our results reveal the 1st shared cellular pathway regulated by multiple ALS genes, and this pathway is ALS genes -> CIITA -> MHC II genes. We obtained the same results in HMC3 cells, a microglia cell line, showing that loss of the MHC II pathway extends to an ALS-relevant cell type in the central nervous system (CNS). Furthermore, the MHC II pathway is downregulated in hematopoietic progenitor cells (HPCs) bearing the ALS FUSR495X mutation. This observation may be highly significant to ALS pathogenesis as HPCs give rise to a multitude of CNS-specific and systemic immune cells, both of which have known or suspected roles in ALS. Together, our data raise the possibility that loss of the MHC II pathway in a large range of immune cells results in global failure of the immune system to protect motor neurons from damage that leads to the disease. Consequently, CIITA and the other genes in the MHC II pathway may be important new therapeutic targets for the disease.

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Contribution of CNS and extra-CNS infections to neurodegeneration: a narrative review

Kettunen,

Koistinaho,

Rolova

2024

J Neuroinflammation

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Central nervous system infections have been suggested as a possible cause for neurodegenerative diseases, particularly sporadic cases. They trigger neuroinflammation which is considered integrally involved in neurodegenerative processes. In this review, we will look at data linking a variety of viral, bacterial, fungal, and protozoan infections to Alzheimer’s disease, Parkinson’s disease, amyotrophic lateral sclerosis, multiple sclerosis and unspecified dementia. This narrative review aims to bring together a broad range of data currently supporting the involvement of central nervous system infections in the development of neurodegenerative diseases. The idea that no single pathogen or pathogen group is responsible for neurodegenerative diseases will be discussed. Instead, we suggest that a wide range of susceptibility factors may make individuals differentially vulnerable to different infectious pathogens and subsequent pathologies.

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Lateral amyotrophic sclerosis-like onset after combined antiretroviral treatment initiation

Cited by 4 publications

References 11 publications

Causal ALS genes impact the MHC class II antigen presentation pathway

Causal ALS genes impact the MHC class II antigen presentation pathway

Three ALS genes regulate expression of the MHC class II antigen presentation pathway

Contribution of CNS and extra-CNS infections to neurodegeneration: a narrative review

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