Contributions
Abstract: P1091
Type: Poster Sessions
Abstract Category: Pathology and pathogenesis of MS - Neurobiology
Changes in gene expression that occur across the central nervous system (CNS) during neurological diseases do not address the heterogeneity of cell types from one CNS region to another and are complicated by alterations in cellular composition during disease. Multiple sclerosis (MS) is multifocal, characterized by distinct disabilities affecting walking, vision, and cognition. Molecular mechanisms underlying distinct disabilities may differ based on the neurological pathway involved. Discovery of neuroprotective treatments optimized for each disability may be more effective than nonspecific treatments aiming to reduce a composite of different disabilities in MS clinical trials.
Here, a cell-specific and region-specific transcriptomics approach was used to determine gene expression changes in astrocytes in the most widely used MS model, experimental autoimmune encephalomyelitis (EAE).
Astrocyte specific RNAs from various neuroanatomic regions were attained using RiboTag technology. Sequencing and bioinformatics analyses identified gene expression pathways altered in astrocytes, with validation at the protein level by immunohistochemistry. Treatment to reverse gene expression was used to improve disability based on neuroanatomic region. MS autopsy tissues were used to translate findings from EAE to MS.
EAE induced gene expression changes differed between neuroanatomic regions when comparing astrocytes from spinal cord, cerebellum, cerebral cortex and hippocampus. The top gene pathways that were changed in astrocytes from spinal cord involved decreases expression of cholesterol synthesis genes, while immune pathway gene expression in astrocytes was increased. Optic nerve from EAE and optic chiasm from MS also showed decreased cholesterol synthesis gene expression. A treatment to increase cholesterol synthesis and transport in astrocytes improved clinical scores and spared synapses and axons.
This is proof-of-concept that a cell-specific and region-specific gene expression approach can provide potential treatment targets in distinct neuroanatomic regions. Altered cholesterol synthesis gene expression in astrocytes in spinal cord and optic nerve was identified as a potential target for walking and visual disabilities, respectively. This disability-specific discovery approach represents a novel strategy for finding neuroprotective treatments for multifocal neurodegenerative diseases.
Disclosure: Rhonda Voskuhl: Nothing to disclose
Yuichiro Itoh: Nothing to disclose
Alessia Tassoni: Nothing to disclose
Emily Ren: Nothing to disclose
Max Kaito: Nothing to disclose
Ai Ohno: Nothing to disclose
Yan Ao: Nothing to disclose
Vista Farkhondeh: Nothing to disclose
Hadley Johnsonbaugh: Nothing to disclose
Josh Burda: Nothing to disclose
Michael V. Sofroniew: Nothing to disclose
Noriko Itoh: Nothing to disclose
Abstract: P1091
Type: Poster Sessions
Abstract Category: Pathology and pathogenesis of MS - Neurobiology
Changes in gene expression that occur across the central nervous system (CNS) during neurological diseases do not address the heterogeneity of cell types from one CNS region to another and are complicated by alterations in cellular composition during disease. Multiple sclerosis (MS) is multifocal, characterized by distinct disabilities affecting walking, vision, and cognition. Molecular mechanisms underlying distinct disabilities may differ based on the neurological pathway involved. Discovery of neuroprotective treatments optimized for each disability may be more effective than nonspecific treatments aiming to reduce a composite of different disabilities in MS clinical trials.
Here, a cell-specific and region-specific transcriptomics approach was used to determine gene expression changes in astrocytes in the most widely used MS model, experimental autoimmune encephalomyelitis (EAE).
Astrocyte specific RNAs from various neuroanatomic regions were attained using RiboTag technology. Sequencing and bioinformatics analyses identified gene expression pathways altered in astrocytes, with validation at the protein level by immunohistochemistry. Treatment to reverse gene expression was used to improve disability based on neuroanatomic region. MS autopsy tissues were used to translate findings from EAE to MS.
EAE induced gene expression changes differed between neuroanatomic regions when comparing astrocytes from spinal cord, cerebellum, cerebral cortex and hippocampus. The top gene pathways that were changed in astrocytes from spinal cord involved decreases expression of cholesterol synthesis genes, while immune pathway gene expression in astrocytes was increased. Optic nerve from EAE and optic chiasm from MS also showed decreased cholesterol synthesis gene expression. A treatment to increase cholesterol synthesis and transport in astrocytes improved clinical scores and spared synapses and axons.
This is proof-of-concept that a cell-specific and region-specific gene expression approach can provide potential treatment targets in distinct neuroanatomic regions. Altered cholesterol synthesis gene expression in astrocytes in spinal cord and optic nerve was identified as a potential target for walking and visual disabilities, respectively. This disability-specific discovery approach represents a novel strategy for finding neuroprotective treatments for multifocal neurodegenerative diseases.
Disclosure: Rhonda Voskuhl: Nothing to disclose
Yuichiro Itoh: Nothing to disclose
Alessia Tassoni: Nothing to disclose
Emily Ren: Nothing to disclose
Max Kaito: Nothing to disclose
Ai Ohno: Nothing to disclose
Yan Ao: Nothing to disclose
Vista Farkhondeh: Nothing to disclose
Hadley Johnsonbaugh: Nothing to disclose
Josh Burda: Nothing to disclose
Michael V. Sofroniew: Nothing to disclose
Noriko Itoh: Nothing to disclose