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| http://dx.doi.org/10.1242/dmm.028696 | DOI Listing |
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Rapid iPSC inclusionopathy models shed light on formation, consequence, and molecular subtype of α-synuclein inclusions.
Neuron
September 2024
Ann Romney Center for Neurologic Diseases, Brigham and Women's Hospital, Boston, MA, USA; Division of Movement Disorders, American Parkinson Disease Association (APDA) Center for Advanced Research and MSA Center of Excellence, Department of Neurology, Brigham and Women's Hospital, Boston, MA, USA; Harvard Medical School, Boston, MA, USA; The Broad Institute of MIT and Harvard, Cambridge, MA, USA; Aligning Science Across Parkinson's (ASAP) Collaborative Research Network, Chevy Chase, MD, USA; Harvard Stem Cell Institute, Cambridge, MA, USA. Electronic address:
Article Synopsis
- The study investigates protein-rich inclusions in neurodegeneration, noting that current iPSC models lack reproducibility and speed in developing these inclusions.
- Researchers created new iPSC models that allow for rapid production of CNS cells with proteins prone to aggregation, enabling the tracking of inclusions at a single level.
- They identified various inclusion types with differing effects on neuron survival and isolated proteins that could influence toxicity, paving the way for improved drug development for neurodegenerative diseases.
An HSF1-JMJD6-HSP feedback circuit promotes cell adaptation to proteotoxic stress.
Proc Natl Acad Sci U S A
July 2024
Department of Biochemistry and Molecular Genetics, Northwestern University Feinberg School of Medicine, Chicago, IL 60611.
Heat Shock Factor 1 (HSF1) is best known as the master transcriptional regulator of the heat-shock response (HSR), a conserved adaptive mechanism critical for protein homeostasis (proteostasis). Combining a genome-wide RNAi library with an HSR reporter, we identified Jumonji domain-containing protein 6 (JMJD6) as an essential mediator of HSF1 activity. In follow-up studies, we found that JMJD6 is itself a noncanonical transcriptional target of HSF1 which acts as a critical regulator of proteostasis.
View Article and Find Full Text PDFDeep sequencing of proteotoxicity modifier genes uncovers a Presenilin-2/beta-amyloid-actin genetic risk module shared among alpha-synucleinopathies.
bioRxiv
March 2024
Division of Movement Disorders, Department of Neurology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA.
Article Synopsis
- Research is exploring whether neurodegenerative diseases caused by similar protein misfolding share genetic risk factors, but traditional studies lack the power to conclusively determine this.
- By selecting patients based on their specific protein aggregation rather than just their clinical diagnosis, researchers can better identify genetic variants associated with diseases like Parkinson's and Alzheimer's.
- The study finds that genetic modifiers related to alpha-synuclein and beta-amyloid contribute to shared risk factors in neurodegenerative diseases, indicating common underlying mechanisms across different conditions.
The Parkinson's disease protein alpha-synuclein is a modulator of processing bodies and mRNA stability.
Cell
June 2022
Ann Romney Center for Neurologic Diseases, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA; Division of Movement Disorders, Department of Neurology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA; Aligning Science Across Parkinson's (ASAP) Collaborative Research Network, Chevy Chase, MD 20815, USA; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Harvard Stem Cell Institute, Cambridge, MA 02138, USA. Electronic address:
Alpha-synuclein (αS) is a conformationally plastic protein that reversibly binds to cellular membranes. It aggregates and is genetically linked to Parkinson's disease (PD). Here, we show that αS directly modulates processing bodies (P-bodies), membraneless organelles that function in mRNA turnover and storage.
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