Dataset Information

?-Synuclein and astrocytes: tracing the pathways from homeostasis to neurodegeneration in Lewy body disease.

ABSTRACT: ?-Synuclein is a soluble protein that is present in abundance in the brain, though its normal function in the healthy brain is poorly defined. Intraneuronal inclusions of ?-synuclein, commonly referred to as Lewy pathology, are pathological hallmarks of a spectrum of neurodegenerative disorders referred to as ?-synucleinopathies. Though ?-synuclein is expressed predominantly in neurons, ?-synuclein aggregates in astrocytes are a common feature in these neurodegenerative diseases. How and why ?-synuclein ends up in the astrocytes and the consequences of this dysfunctional proteostasis in immune cells is a major area of research that can have far-reaching implications for future immunobiotherapies in ?-synucleinopathies. Accumulation of aggregated ?-synuclein can disrupt astrocyte function in general and, more importantly, can contribute to neurodegeneration in ?-synucleinopathies through various pathways. Here, we summarize our current knowledge on how astrocytic ?-synucleinopathy affects CNS function in health and disease and propose a model of neuroglial connectome altered by ?-synuclein proteostasis that might be amenable to immune-based therapies.

SUBMITTER: Sorrentino ZA

PROVIDER: S-EPMC6571045 | biostudies-literature | 2019 Jul

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

α-Synuclein and astrocytes: tracing the pathways from homeostasis to neurodegeneration in Lewy body disease.

Sorrentino Zachary A ZA Giasson Benoit I BI Chakrabarty Paramita P

Acta neuropathologica 20190223 1

α-Synuclein is a soluble protein that is present in abundance in the brain, though its normal function in the healthy brain is poorly defined. Intraneuronal inclusions of α-synuclein, commonly referred to as Lewy pathology, are pathological hallmarks of a spectrum of neurodegenerative disorders referred to as α-synucleinopathies. Though α-synuclein is expressed predominantly in neurons, α-synuclein aggregates in astrocytes are a common feature in these neurodegenerative diseases. How and why α-s ...[more]

PMID: 30798354

Similar Datasets

Project description:Autosomal dominant variants in LRP10 have been identified in patients with Lewy body diseases (LBDs), including Parkinson's disease (PD), Parkinson's disease-dementia (PDD), and dementia with Lewy bodies (DLB). Nevertheless, there is little mechanistic insight into the role of LRP10 in disease pathogenesis. In the brains of control individuals, LRP10 is typically expressed in non-neuronal cells like astrocytes and neurovasculature, but in idiopathic and genetic cases of PD, PDD, and DLB, it is also present in α-synuclein-positive neuronal Lewy bodies. These observations raise the questions of what leads to the accumulation of LRP10 in Lewy bodies and whether a possible interaction between LRP10 and α-synuclein plays a role in disease pathogenesis. Here, we demonstrate that wild-type LRP10 is secreted via extracellular vesicles (EVs) and can be internalised via clathrin-dependent endocytosis. Additionally, we show that LRP10 secretion is highly sensitive to autophagy inhibition, which induces the formation of atypical LRP10 vesicular structures in neurons in human-induced pluripotent stem cells (iPSC)-derived brain organoids. Furthermore, we show that LRP10 overexpression leads to a strong induction of monomeric α-synuclein secretion, together with time-dependent, stress-sensitive changes in intracellular α-synuclein levels. Interestingly, patient-derived astrocytes carrying the c.1424 + 5G > A LRP10 variant secrete aberrant high-molecular-weight species of LRP10 in EV-free media fractions. Finally, we show that this truncated patient-derived LRP10 protein species (LRP10splice) binds to wild-type LRP10, reduces LRP10 wild-type levels, and antagonises the effect of LRP10 on α-synuclein levels and distribution. Together, this work provides initial evidence for a possible functional role of LRP10 in LBDs by modulating intra- and extracellular α-synuclein levels, and pathogenic mechanisms linked to the disease-associated c.1424 + 5G > A LRP10 variant, pointing towards potentially important disease mechanisms in LBDs.

Dataset Information

?-Synuclein and astrocytes: tracing the pathways from homeostasis to neurodegeneration in Lewy body disease.

Publications

α-Synuclein and astrocytes: tracing the pathways from homeostasis to neurodegeneration in Lewy body disease.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets