The Role of Astrocyte Dysfunction in Parkinson’s Disease Pathogenesis

Booth, Heather; Hirst, Warren D.; Wade‐Martins, Richard

doi:10.1016/j.tins.2017.04.001

Cited by 485 publications

(435 citation statements)

References 99 publications

(147 reference statements)

Supporting

Mentioning

418

Contrasting

Unclassified

Order By: Relevance

“…[42] Due to its involvement in familial and sporadic PD and the presence of a drugable kinase domain, LRRK2 has become an attractive pharmacological target. [45] Cocultures of various iPSC-derived neural cells will be important to assess cell and noncell autonomous effects. [43] Subsequent investigations also pointed to protein expression levels, focusing on posttranslational modifications such as phosphorylation at serine residues Ser910 and Ser935, located prior to the leucine-rich domain of LRRK2.…”

Section: Discussionmentioning

confidence: 99%

3D Cultures of Parkinson's Disease‐Specific Dopaminergic Neurons for High Content Phenotyping and Drug Testing

et al. 2018

View full text Add to dashboard Cite

Parkinson's disease (PD)‐specific neurons, grown in standard 2D cultures, typically only display weak endophenotypes. The cultivation of PD patient‐specific neurons, derived from induced pluripotent stem cells carrying the LRRK2‐G2019S mutation, is optimized in 3D microfluidics. The automated image analysis algorithms are implemented to enable pharmacophenomics in disease‐relevant conditions. In contrast to 2D cultures, this 3D approach reveals robust endophenotypes. High‐content imaging data show decreased dopaminergic differentiation and branching complexity, altered mitochondrial morphology, and increased cell death in LRRK2‐G2019S neurons compared to isogenic lines without using stressor agents. Treatment with the LRRK2 inhibitor 2 (Inh2) rescues LRRK2‐G2019S‐dependent dopaminergic phenotypes. Strikingly, a holistic analysis of all studied features shows that the genetic background of the PD patients, and not the LRRK2‐G2019S mutation, constitutes the strongest contribution to the phenotypes. These data support the use of advanced in vitro models for future patient stratification and personalized drug development.

show abstract

Section: Discussionmentioning

confidence: 99%

3D Cultures of Parkinson's Disease‐Specific Dopaminergic Neurons for High Content Phenotyping and Drug Testing

et al. 2018

View full text Add to dashboard Cite

show abstract

“…Pathologically, PD is characterized by the deposition of misfolded and ubiquitinated α‐synuclein fibrils in neurons, which are thought to cause neuronal toxicity (Poewe et al, ). Nonfibrillar α‐synuclein accumulation was also observed in the cytoplasm of cortical and subcortical protoplasmic, but not fibrous, astrocytes in PD patients (Booth et al, ; Braak, Sastre, & Del Tredici, ; Song et al, ; Wakabayashi, Hayashi, Yoshimoto, Kudo, & Takahashi, ). Of note, the presence of these inclusions did not correlate with astrogliosis, which was only mild in the SN (Song et al, ).…”

Section: Ipscs Derived Astrocytes As Disease Model: a New Platform Tomentioning

confidence: 99%

“…Less well established, however, is the role that these cells play in disease as both toxic gain of function and LOF have been hypothesized (Liddelow et al, ; Oksanen et al, ). Recently, it was found that genes expressed by human astrocytes are enriched for CNS disease‐linked genes (Booth, Hirst, & Wade‐Martins, ; Kelley, Nakao‐Inoue, Molofsky, & Oldham, ; Zhang et al, ). In particular, single cell RNAseq in human brain revealed that there is an enrichment of genes involved in most neurodegenerative diseases, which are expressed by astrocyte and microglia (Cuevas‐Diaz Duran, Wang, Zheng, Deneen, & Wu, ; Kelley et al, ).…”

Section: Ipscs Derived Astrocytes As Disease Model: a New Platform Tomentioning

confidence: 99%

An update on human astrocytes and their role in development and disease

Majo

Koontz

Rowitch

et al. 2020

Glia

View full text Add to dashboard Cite

Human astrocytes provide trophic as well as structural support to the surrounding brain cells. Furthermore, they have been implicated in many physiological processes important for central nervous system function. Traditionally astrocytes have been considered to be a homogeneous class of cells, however, it has increasingly become more evident that astrocytes can have very different characteristics in different regions of the brain, or even within the same region. In this review we will discuss the features of human astrocytes, their heterogeneity, and their generation during neurodevelopment and the extraordinary progress that has been made to model these fascinating cells in vitro, mainly from induced pluripotent stem cells. Astrocytes' role in disease will also be discussed with a particular focus on their role in neurodegenerative disorders. As outlined here, astrocytes are important for the homeostasis of the central nervous system and understanding their regional specificity is a priority to elucidate the complexity of the human brain.

show abstract

“…Inflammation involving reactive astrocytes is known to contribute to progression of PD 44 . Involvement of nAChRs in PD was suggested by epidemiological studies showing reduced occurrence of this disease in smokers and altered expression of nAChRs in patients and disease models 4,45 .…”

Section: Ric-3 and Diseases Of The Central Nervous Systemmentioning

confidence: 99%

“…Thus, the mechanisms of action of PD-associated RIC-3 mutations in this disease need to be identified. But, the demonstrated effects of these mutations on α7 nAChR surface expression 40 , the known role of this nAChR in regulating inflammation (above), and contribution of inflammation to neurodegenerative processes occurring in PD 44,50 , suggest a mechanism involving decreased activity of the cholinergic anti-inflammatory pathway as a mechanism explaining effects of both PD-associated RIC-3 mutations and nicotine on PD progression.…”

Section: Ric-3 and Diseases Of The Central Nervous Systemmentioning

confidence: 99%

RIC-3, a potential target for regulating cholinergic signaling and inflammation

Treinin¹

2017

J Immunological Sci

View full text Add to dashboard Cite

The nic�� acetylcholine receptor (nAChR) gene family encodes for subunits of acetylcholine gated ion channels. These receptors are expressed widely and have many �� including an�� tory e� ects mediated by the α7 nAChR, as part of the cholinergic an�� tory pathway, in immune cells, microglia and astrocytes. Matura�� of α7 nAChRs into �� ligand-gated ion channels in the plasma membrane is a complex process likely to require the RIC-3 protein. This endoplasmic re�� resident chaperone a� ects matura�� of �� nAChRs, but its inter�� with these receptors and its e� ects on their matura�� er for �� erent nAChRs. Moreover, these inter�� and e� ects are regulated by �� mechanisms. Gene�� analysis has implicated RIC-3 in the neuroin��tory disease �� Sclerosis (MS), and in the neurodegenera� e Parkinson's disease (PD). Neuroin�� contributes to the progression of neurodegenera� e diseases including PD. This informa�� combines to suggest that RIC-3 may contribute to progression of both MS and PD via its e� ects on the α7 nAChR and the cholinergic an� in��tory pathway. Furthermore, we suggest that mechanisms regula�� RIC-3 expr�� y have a role in controlling in�� The nicotinic acetylcholine receptor familyThe nicotinic acetylcholine receptors (nAChRs) are a large and diverse family of acetylcholine-gated ion channels. In mammals this family is composed of nine alpha subunits and seven non-alpha subunits. These subunits assemble to form mostly heteromeric (α7 and α9 nAChR subunits can form homomeric receptors), cation-selective channels having diverse properties and expression patterns. In skeletal-muscles and in the autonomic nervous system nAChRs mediate excitatory synaptic transmission. However, in the central nervous system (CNS) nAChRs do not usually mediate synaptic transmission and instead play modulatory roles, including a role in regulating neurotransmitter release, reviewed by Dani and Bertrand 1. In addition to being expressed in muscles and neurons, nAChRs are also found in multiple types of non-excitable cells where they affect migration, differentiation, proliferation, and signal transduction 2 .CNS-expressed nAChRs have been implicated in memory, cognition, addiction, and several neurodegenerative diseases. Evidence for these functions comes from the addictive effects of tobacco-derived nicotine and from epidemiological studies linking tobacco smoking to neurodegenerative diseases such as schizophrenia and Parkinson's disease (reviewed by Dani and

show abstract

The Role of Astrocyte Dysfunction in Parkinson’s Disease Pathogenesis

Cited by 485 publications

References 99 publications

3D Cultures of Parkinson's Disease‐Specific Dopaminergic Neurons for High Content Phenotyping and Drug Testing

3D Cultures of Parkinson's Disease‐Specific Dopaminergic Neurons for High Content Phenotyping and Drug Testing

An update on human astrocytes and their role in development and disease

RIC-3, a potential target for regulating cholinergic signaling and inflammation

Contact Info

Product

Resources

About