Astrocytic contributions to Huntington's disease pathophysiology
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Astrocytic contributions to Huntington's disease pathophysiology. / Khakh, Baljit S.; Goldman, Steven A.
In: Annals of the New York Academy of Sciences, Vol. 1522, No. 1, 2023, p. 42-59.Research output: Contribution to journal › Review › Research › peer-review
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TY - JOUR
T1 - Astrocytic contributions to Huntington's disease pathophysiology
AU - Khakh, Baljit S.
AU - Goldman, Steven A.
N1 - Publisher Copyright: © 2023 New York Academy of Sciences.
PY - 2023
Y1 - 2023
N2 - Huntington's disease (HD) is a fatal, monogenic, autosomal dominant neurodegenerative disease caused by a polyglutamine-encoding CAG expansion in the huntingtin (HTT) gene that results in mutant huntingtin proteins (mHTT) in cells throughout the body. Although large parts of the central nervous system (CNS) are affected, the striatum is especially vulnerable and undergoes marked atrophy. Astrocytes are abundant within the striatum and contain mHTT in HD, as well as in mouse models of the disease. We focus on striatal astrocytes and summarize how they participate in, and contribute to, molecular pathophysiology and disease-related phenotypes in HD model mice. Where possible, reference is made to pertinent astrocyte alterations in human HD. Astrocytic dysfunctions related to cellular morphology, extracellular ion and neurotransmitter homeostasis, and metabolic support all accompany the development and progression of HD, in both transgenic mouse and human cellular and chimeric models of HD. These findings reveal the potential for the therapeutic targeting of astrocytes so as to restore synaptic as well as tissue homeostasis in HD. Elucidation of the mechanisms by which astrocytes contribute to HD pathogenesis may inform a broader understanding of the role of glial pathology in neurodegenerative disorders and, by so doing, enable new strategies of glial-directed therapeutics.
AB - Huntington's disease (HD) is a fatal, monogenic, autosomal dominant neurodegenerative disease caused by a polyglutamine-encoding CAG expansion in the huntingtin (HTT) gene that results in mutant huntingtin proteins (mHTT) in cells throughout the body. Although large parts of the central nervous system (CNS) are affected, the striatum is especially vulnerable and undergoes marked atrophy. Astrocytes are abundant within the striatum and contain mHTT in HD, as well as in mouse models of the disease. We focus on striatal astrocytes and summarize how they participate in, and contribute to, molecular pathophysiology and disease-related phenotypes in HD model mice. Where possible, reference is made to pertinent astrocyte alterations in human HD. Astrocytic dysfunctions related to cellular morphology, extracellular ion and neurotransmitter homeostasis, and metabolic support all accompany the development and progression of HD, in both transgenic mouse and human cellular and chimeric models of HD. These findings reveal the potential for the therapeutic targeting of astrocytes so as to restore synaptic as well as tissue homeostasis in HD. Elucidation of the mechanisms by which astrocytes contribute to HD pathogenesis may inform a broader understanding of the role of glial pathology in neurodegenerative disorders and, by so doing, enable new strategies of glial-directed therapeutics.
KW - astrocyte
KW - glia
KW - Huntington's disease
KW - neuron
KW - striatum
U2 - 10.1111/nyas.14977
DO - 10.1111/nyas.14977
M3 - Review
C2 - 36864567
AN - SCOPUS:85152170238
VL - 1522
SP - 42
EP - 59
JO - Annals of The Lyceum of Natural History of New York
JF - Annals of The Lyceum of Natural History of New York
SN - 0077-8923
IS - 1
ER -
ID: 371284167