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Glial cells as intrinsic components of non-cell-autonomous neurodegenerative disease

Abstract

A lesson from dominantly inherited forms of diverse neurodegenerative diseases, including amyotrophic lateral sclerosis, spinocerebellar ataxia and Huntington's disease, is that the selective dysfunction or death of the neuronal population most at risk in each disease is not mediated solely by damage from the mutant protein within the target neurons. The disease-causing toxic process, which in each case is caused by mutation in a gene that is widely or ubiquitously expressed, involves damage done by mutant proteins within the non-neuronal glial cells of the central nervous system, especially astrocytes and microglia. The disease mechanism is non-cell-autonomous, with toxicity derived from glia as a prominent contributor driving disease progression and in some instances even disease initiation.

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Figure 1: Insights from animal models of diverse human neurodegenerative diseases indicate that disease mechanisms are non-cell-autonomous, requiring the convergence of damage within the vulnerable neurons and their neighboring glial cells.
Figure 2: Non-cell-autonomous neurotoxicity in ALS.
Figure 3: Non-cell-autonomous, glia-derived toxicity can lead to degeneration of Purkinje neurons in SCA7.

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Correspondence to Don W Cleveland.

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Lobsiger, C., Cleveland, D. Glial cells as intrinsic components of non-cell-autonomous neurodegenerative disease. Nat Neurosci 10, 1355–1360 (2007). https://doi.org/10.1038/nn1988

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