Elevated ATG5 expression in autoimmune demyelination and multiple sclerosis

Mehrdad Alirezaei; Howard S. Fox; Claudia T. Flynn; Craig S. Moore; Andrea L.O. Hebb; Ricardo F. Frausto; Virender Bhan; William B. Kiosses; J. Lindsay Whitton; George S. Robertson; Stephen J. Crocker

doi:10.4161/auto.5.2.7348

Elevated ATG5 expression in autoimmune demyelination and multiple sclerosis

Mehrdad Alirezaei, Howard S. Fox, Claudia T. Flynn, Craig S. Moore, Andrea L.O. Hebb, Ricardo F. Frausto, Virender Bhan, William B. Kiosses, J. Lindsay Whitton, George S. Robertson, Stephen J. Crocker

Medicine

Research output: Contribution to journal › Article › peer-review

137 Citations (Scopus)

Abstract

Multiple sclerosis (MS) is an inflammatory central nervous system (CNS) disorder characterized by T cell-mediated demyelination. In MS, prolonged T cell survival and increased T cell proliferation have been linked to disease relapse and progression. Recently, the autophagy-related gene 5 (Atg5) has been shown to modulate T cell survival. In this study, we examined the expression of Atg5 using both a mouse model of autoimmune demyelination as well as blood and brain tissues from MS cases. Quantitative real-time PCR analysis of RNA isolated from blood samples of experimental autoimmune encephalomyelitis (EAE) mice revealed a strong correlation between Atg5 expression and clinical disability. Analysis of protein extracted from these cells confirmed both upregulation and post-translational modification of Atg5, the latter of which was positively correlated with EAE severity. Analysis of RNA extracted from T cells isolated by negative selection indicated that Atg5 expression was significantly elevated in individuals with active relapsing-remitting MS compared to non-diseased controls. Brain tissue sections from relapsing-remitting MS cases examined by immunofluorescent histochemistry suggested that encephalitogenic T cells are a source of Atg5 expression in MS brain samples. Together these data suggest that increased T cell expression of Atg5 may contribute to inflammatory demyelination in MS.

Original language	English
Pages (from-to)	152-158
Number of pages	7
Journal	Autophagy
Volume	5
Issue number	2
DOIs	https://doi.org/10.4161/auto.5.2.7348
Publication status	Published - Feb 16 2009

Bibliographical note

Funding Information:
We are grateful for the generous gift of the Atg5 antibody (SO4) from Dr. N. Mizushima (Department of Physiology and Cell Biology; Tokyo Medical and Dental University, Japan). This work was supported by grants from the National Institutes of Health (AI-27028 to J.L.W; DA024467, MH072477 and MH062261 to H.S.F; and NRSA F32 NS048767 to M.A), Genome Canada (G.S.R), MS Society of Canada Post-Doctoral Fellowship (ALOH), MS Society of Canada Studentship (C.S.M), a Career Transition Fellowship from the National Multiple Sclerosis Society (NMSS:TA 3021A1/1) and startup funds from the University of Connecticut (both to S.J.C). We thank Michelle Zandonnati for technical assistance. We also thank the specimen repositories for brain specimens, obtained from the Human Brain and Spinal Fluid Resource Center, VA West Los Angeles Healthcare Center, which is sponsored by NINDS/NIMH, NMSS and the Department of Veterans Affairs. This is manuscript # 19308 from The Scripps Research Institute.

ASJC Scopus Subject Areas

Molecular Biology
Cell Biology

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title = "Elevated ATG5 expression in autoimmune demyelination and multiple sclerosis",

abstract = "Multiple sclerosis (MS) is an inflammatory central nervous system (CNS) disorder characterized by T cell-mediated demyelination. In MS, prolonged T cell survival and increased T cell proliferation have been linked to disease relapse and progression. Recently, the autophagy-related gene 5 (Atg5) has been shown to modulate T cell survival. In this study, we examined the expression of Atg5 using both a mouse model of autoimmune demyelination as well as blood and brain tissues from MS cases. Quantitative real-time PCR analysis of RNA isolated from blood samples of experimental autoimmune encephalomyelitis (EAE) mice revealed a strong correlation between Atg5 expression and clinical disability. Analysis of protein extracted from these cells confirmed both upregulation and post-translational modification of Atg5, the latter of which was positively correlated with EAE severity. Analysis of RNA extracted from T cells isolated by negative selection indicated that Atg5 expression was significantly elevated in individuals with active relapsing-remitting MS compared to non-diseased controls. Brain tissue sections from relapsing-remitting MS cases examined by immunofluorescent histochemistry suggested that encephalitogenic T cells are a source of Atg5 expression in MS brain samples. Together these data suggest that increased T cell expression of Atg5 may contribute to inflammatory demyelination in MS.",

author = "Mehrdad Alirezaei and Fox, {Howard S.} and Flynn, {Claudia T.} and Moore, {Craig S.} and Hebb, {Andrea L.O.} and Frausto, {Ricardo F.} and Virender Bhan and Kiosses, {William B.} and Whitton, {J. Lindsay} and Robertson, {George S.} and Crocker, {Stephen J.}",

note = "Funding Information: We are grateful for the generous gift of the Atg5 antibody (SO4) from Dr. N. Mizushima (Department of Physiology and Cell Biology; Tokyo Medical and Dental University, Japan). This work was supported by grants from the National Institutes of Health (AI-27028 to J.L.W; DA024467, MH072477 and MH062261 to H.S.F; and NRSA F32 NS048767 to M.A), Genome Canada (G.S.R), MS Society of Canada Post-Doctoral Fellowship (ALOH), MS Society of Canada Studentship (C.S.M), a Career Transition Fellowship from the National Multiple Sclerosis Society (NMSS:TA 3021A1/1) and startup funds from the University of Connecticut (both to S.J.C). We thank Michelle Zandonnati for technical assistance. We also thank the specimen repositories for brain specimens, obtained from the Human Brain and Spinal Fluid Resource Center, VA West Los Angeles Healthcare Center, which is sponsored by NINDS/NIMH, NMSS and the Department of Veterans Affairs. This is manuscript # 19308 from The Scripps Research Institute.",

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doi = "10.4161/auto.5.2.7348",

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AU - Alirezaei, Mehrdad

AU - Fox, Howard S.

AU - Flynn, Claudia T.

AU - Moore, Craig S.

AU - Hebb, Andrea L.O.

AU - Frausto, Ricardo F.

AU - Bhan, Virender

AU - Kiosses, William B.

AU - Whitton, J. Lindsay

AU - Robertson, George S.

AU - Crocker, Stephen J.

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N2 - Multiple sclerosis (MS) is an inflammatory central nervous system (CNS) disorder characterized by T cell-mediated demyelination. In MS, prolonged T cell survival and increased T cell proliferation have been linked to disease relapse and progression. Recently, the autophagy-related gene 5 (Atg5) has been shown to modulate T cell survival. In this study, we examined the expression of Atg5 using both a mouse model of autoimmune demyelination as well as blood and brain tissues from MS cases. Quantitative real-time PCR analysis of RNA isolated from blood samples of experimental autoimmune encephalomyelitis (EAE) mice revealed a strong correlation between Atg5 expression and clinical disability. Analysis of protein extracted from these cells confirmed both upregulation and post-translational modification of Atg5, the latter of which was positively correlated with EAE severity. Analysis of RNA extracted from T cells isolated by negative selection indicated that Atg5 expression was significantly elevated in individuals with active relapsing-remitting MS compared to non-diseased controls. Brain tissue sections from relapsing-remitting MS cases examined by immunofluorescent histochemistry suggested that encephalitogenic T cells are a source of Atg5 expression in MS brain samples. Together these data suggest that increased T cell expression of Atg5 may contribute to inflammatory demyelination in MS.

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Elevated ATG5 expression in autoimmune demyelination and multiple sclerosis

Abstract

Bibliographical note

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