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Activin A is essential for neurogenesis following neurodegeneration.

ABSTRACT: It has long been proposed that excitotoxicity contributes to nerve cell death in neurodegenerative diseases. Activin A, a member of the transforming growth factor-beta superfamily, is expressed by neurons following excitotoxicity. We show for the first time that this activin A expression is essential for neurogenesis to proceed following neurodegeneration. We found that intraventricular infusion of activin A increased the number of newborn neurons in the dentate gyrus, CA3, and CA1 layers of the normal adult hippocampus and also, following lipopolysaccharide administration, had a potent inhibitory effect on gliosis in vivo and on microglial proliferation in vivo and in vitro. Consistent with the role of activin A in regulating central nervous system inflammation and neurogenesis, intraventricular infusion of follistatin, an activin A antagonist, profoundly impaired neurogenesis and increased the number of microglia and reactive astrocytes following onset of kainic acid-induced neurodegeneration. These results show that inhibiting endogenous activin A is permissive for a potent underlying inflammatory response to neurodegeneration. We demonstrate that the anti-inflammatory actions of activin A account for its neurogenic effects following neurodegeneration because co-administration of nonsteroidal anti-inflammatory drugs reversed follistatin's inhibitory effects on neurogenesis in vivo. Our work indicates that activin A, perhaps working in conjunction with other transforming growth factor-beta superfamily molecules, is essential for neurogenesis in the adult central nervous system following excitotoxic neurodegeneration and suggests that neurons can regulate regeneration by suppressing the inflammatory response, a finding with implications for understanding and treating acute and chronic neurodegenerative diseases.

SUBMITTER: Abdipranoto-Cowley A

PROVIDER: S-EPMC2733378 | biostudies-literature | 2009 Jun

REPOSITORIES: biostudies-literature

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Activin A is essential for neurogenesis following neurodegeneration.

Abdipranoto-Cowley Andrea A Park Jin Sung JS Croucher David D Daniel James J Henshall Susan S Galbraith Sally S Mervin Kyle K Vissel Bryce B

Stem cells (Dayton, Ohio) 20090601 6

It has long been proposed that excitotoxicity contributes to nerve cell death in neurodegenerative diseases. Activin A, a member of the transforming growth factor-beta superfamily, is expressed by neurons following excitotoxicity. We show for the first time that this activin A expression is essential for neurogenesis to proceed following neurodegeneration. We found that intraventricular infusion of activin A increased the number of newborn neurons in the dentate gyrus, CA3, and CA1 layers of the ...[more]

PMID: 19489097

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Project description:Maintenance of protein homeostasis is vitally important in post-mitotic cells, particularly neurons. Neurodegenerative diseases such as polyglutamine expansion disorders-like Huntington's disease or spinocerebellar ataxia (SCA), Alzheimer's disease, fronto-temporal dementia (FTD), amyotrophic lateral sclerosis (ALS) and Parkinson's disease-are often characterized by the presence of inclusions of aggregated protein. Neurons contain complex protein networks dedicated to protein quality control and maintaining protein homeostasis, or proteostasis. Molecular chaperones are a class of proteins with prominent roles in maintaining proteostasis, which act to bind and shield hydrophobic regions of nascent or misfolded proteins while allowing correct folding, conformational changes and enabling quality control. There are many different families of molecular chaperones with multiple functions in proteostasis. The DNAJ family of molecular chaperones is the largest chaperone family and is defined by the J-domain, which regulates the function of HSP70 chaperones. DNAJ proteins can also have multiple other protein domains such as ubiquitin-interacting motifs or clathrin-binding domains leading to diverse and specific roles in the cell, including targeting client proteins for degradation via the proteasome, chaperone-mediated autophagy and uncoating clathrin-coated vesicles. DNAJ proteins can also contain ER-signal peptides or mitochondrial leader sequences, targeting them to specific organelles in the cell. In this review, we discuss the multiple roles of DNAJ proteins and in particular focus on the role of DNAJ proteins in protecting against neurodegenerative diseases caused by misfolded proteins. We also discuss the role of DNAJ proteins as direct causes of inherited neurodegeneration via mutations in DNAJ family genes.This article is part of the theme issue 'Heat shock proteins as modulators and therapeutic targets of chronic disease: an integrated perspective'.

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Activin A is essential for neurogenesis following neurodegeneration.

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Activin A is essential for neurogenesis following neurodegeneration.

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