Astrocytic expression of the chaperone DNAJB6 results in non-cell autonomous protection in Huntington’s disease

Bason, Matteo; Meister-Broekema, Melanie; Alberts, Niels; Dijkers, Pascale F.; Bergink, Steven; Sibon, Ody C. M.; Kampinga, Harm H.

doi:10.1016/j.nbd.2018.10.017

Cited by 23 publications

(17 citation statements)

References 43 publications

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“…Brain-specific DNAJB6b overexpression inhibits inclusion formation, delays disease, and improves motor function in a mouse model of Huntington's disease [53]. Likewise, in Drosophila, the neuronal overexpression of dMRJ or human DNAJB6b protects from polyQ-induced cytotoxicity [54,62] and, remarkably, astrocytic DNAJB6b expression also provided non-cell-autonomous protection against neuronally expressed polyQ [62].…”

Section: Antiaggregation and Cytoprotectionmentioning

confidence: 96%

Neuromuscular Diseases Due to Chaperone Mutations: A Review and Some New Results

Sarparanta

Jonson

Kawan

et al. 2020

IJMS

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Skeletal muscle and the nervous system depend on efficient protein quality control, and they express chaperones and cochaperones at high levels to maintain protein homeostasis. Mutations in many of these proteins cause neuromuscular diseases, myopathies, and hereditary motor and sensorimotor neuropathies. In this review, we cover mutations in DNAJB6, DNAJB2, αB-crystallin (CRYAB, HSPB5), HSPB1, HSPB3, HSPB8, and BAG3, and discuss the molecular mechanisms by which they cause neuromuscular disease. In addition, previously unpublished results are presented, showing downstream effects of BAG3 p.P209L on DNAJB6 turnover and localization.

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Section: Antiaggregation and Cytoprotectionmentioning

confidence: 96%

Neuromuscular Diseases Due to Chaperone Mutations: A Review and Some New Results

Sarparanta

Jonson

Kawan

et al. 2020

IJMS

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“…HSP-mediated extraction of housekeeping proteins or mHTT itself from aggregates is expected to reduce their size, which is consistent with our observations. Therefore, HSP have multiple actions that can in fine protect neurons against mHTT toxicity, as shown in different experimental systems based on HSP overexpression [72][73][74] . Here, we show that neurons rely on the endogenous production of chaperones by astrocytes to reduce mHTT aggregation.…”

Section: Discussionmentioning

confidence: 99%

Reactive astrocytes promote proteostasis in Huntington’s disease through the JAK2-STAT3 pathway

Abjean

Haim

Riquelme-Pérez

et al. 2021

Preprint

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Huntington's disease (HD) is a fatal neurodegenerative disease characterized by striatal neurodegeneration, aggregation of mutant Huntingtin (mHTT) and the presence of reactive astrocytes. Astrocytes are important partners for neurons and engage in a specific reactive response in HD that involves morphological, molecular and functional changes. How reactive astrocytes contribute to HD is still an open question, especially because their reactive state is poorly reproduced in mouse models. Here, we show that the JAK2-STAT3 pathway, a central cascade controlling the reactive response of astrocytes, is activated in the putamen of HD patients. Selective activation of this cascade in astrocytes reduces the number and size of neuronal mHTT aggregates and improves neuronal features in two HD mouse models. Moreover, activation of the JAK2-STAT3 pathway in astrocytes coordinates a transcriptional program that increases their intrinsic proteolytic capacity, through the lysosomes and the ubiquitin-proteasome system, and enhances their production of the co-chaperone DNAJB1, which is released in exosomes. Together, our results show that the JAK2-STAT3 pathway controls a beneficial proteostasis response in reactive astrocytes in HD, which involves bi-directional signalling with neurons to reduce mHTT aggregation and toxicity.

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“…Recently, this idea was explored using a Drosophila model with polyQ expressed in neurons and DNAJB6 expressed in glial cells. The exclusive expression of DNAJB6 in glial cells results in the non-cell-autonomous protection against neurodegeneration and prolongs lifespan (Bason et al, 2019 ). A deeper understanding of how chaperones could alleviate the non-cell-autonomous effects of prion-like proteins could reveal an exciting new therapeutic approach.…”

Section: The Role Of Chaperones In Prion-like Propagationmentioning

confidence: 99%

Molecular Chaperones: A Double-Edged Sword in Neurodegenerative Diseases

Tittelmeier

Nachman

Nussbaum-Krammer

2020

Front. Aging Neurosci.

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Aberrant accumulation of misfolded proteins into amyloid deposits is a hallmark in many age-related neurodegenerative diseases, including Alzheimer’s disease (AD), Parkinson’s disease (PD), Huntington’s disease (HD), and amyotrophic lateral sclerosis (ALS). Pathological inclusions and the associated toxicity appear to spread through the nervous system in a characteristic pattern during the disease. This has been attributed to a prion-like behavior of amyloid-type aggregates, which involves self-replication of the pathological conformation, intercellular transfer, and the subsequent seeding of native forms of the same protein in the neighboring cell. Molecular chaperones play a major role in maintaining cellular proteostasis by assisting the (re)-folding of cellular proteins to ensure their function or by promoting the degradation of terminally misfolded proteins to prevent damage. With increasing age, however, the capacity of this proteostasis network tends to decrease, which enables the manifestation of neurodegenerative diseases. Recently, there has been a plethora of studies investigating how and when chaperones interact with disease-related proteins, which have advanced our understanding of the role of chaperones in protein misfolding diseases. This review article focuses on the steps of prion-like propagation from initial misfolding and self-templated replication to intercellular spreading and discusses the influence that chaperones have on these various steps, highlighting both the positive and adverse consequences chaperone action can have. Understanding how chaperones alleviate and aggravate disease progression is vital for the development of therapeutic strategies to combat these debilitating diseases.

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Astrocytic expression of the chaperone DNAJB6 results in non-cell autonomous protection in Huntington’s disease

Cited by 23 publications

References 43 publications

Neuromuscular Diseases Due to Chaperone Mutations: A Review and Some New Results

Neuromuscular Diseases Due to Chaperone Mutations: A Review and Some New Results

Reactive astrocytes promote proteostasis in Huntington’s disease through the JAK2-STAT3 pathway

Molecular Chaperones: A Double-Edged Sword in Neurodegenerative Diseases

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