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Alexander Goginashvili

Bio: Alexander Goginashvili is an academic researcher from University of California, San Diego. The author has contributed to research in topics: Stress granule & DNA repair. The author has an hindex of 2, co-authored 3 publications receiving 143 citations. Previous affiliations of Alexander Goginashvili include University of California, Berkeley & Ludwig Institute for Cancer Research.

Papers
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Journal ArticleDOI
05 Apr 2017-Neuron
TL;DR: Overall, the findings identify polyglutamine-dependent inhibition of nucleocytoplasmic transport and alteration of nuclear integrity as a central component of Huntington's disease.

176 citations

Journal ArticleDOI
TL;DR: In this paper, the authors discuss how micronuclei are generated, what the consequences are, and what cellular mechanisms can be applied to protect against micronuclearation, with a focus on the effects of DNA degradation.

60 citations

Posted ContentDOI
11 Oct 2021-bioRxiv
TL;DR: The authors showed that transient oxidative stress, proteasome inhibition, or inhibition of ATP-dependent chaperone activity provokes reversible cytoplasmic TDP-43 de-mixing and transition from liquid to gel/solid, independent of RNA binding or stress granules.
Abstract: Summary While the RNA binding protein TDP-43 reversibly phase separates within nuclei into complex droplets (anisosomes) with TDP-43-containing liquid outer shells and liquid centers of HSP70 family chaperones, cytoplasmic aggregates of TDP-43 are hallmarks of multiple neurodegenerative diseases, including ALS. Here we show that transient oxidative stress, proteasome inhibition, or inhibition of HSP70’s ATP-dependent chaperone activity provokes reversible cytoplasmic TDP-43 de-mixing and transition from liquid to gel/solid, independent of RNA binding or stress granules. Isotope labeling mass spectrometry is used to identify that phase separated cytoplasmic TDP-43 is primarily bound by the small heat shock protein HSPB1. Binding is direct, mediated through TDP-43’s RNA binding and low complexity domains. HSPB1 partitions into TDP-43 droplets, inhibits TDP-43 assembly into fibrils, and is essential for disassembly of stress-induced, TDP-43 droplets. Decrease of HSPB1 promotes cytoplasmic TDP-43 de-mixing and mislocalization. HSPB1 depletion is identified within ALS-patient spinal motor neurons containing aggregated TDP-43. These findings identify HSPB1 to be a regulator of cytoplasmic TDP-43 phase separation and aggregation.

1 citations


Cited by
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Journal ArticleDOI
TL;DR: A combination of techniques from cell biology, biophysics, physical chemistry, structural biology, and bioinformatics are starting to help establish the molecular principles of an emerging field, thus paving the way for exciting discoveries, including novel therapeutic approaches for the treatment of age-related disorders.

1,317 citations

Journal ArticleDOI
TL;DR: The possibilities of pharmacological augmentation of the capacity of proteostasis networks hold great promise for delaying the onset of age-related pathologies associated with proteome deterioration and for extending healthspan.
Abstract: Ageing is a major risk factor for the development of many diseases, prominently including neurodegenerative disorders such as Alzheimer disease and Parkinson disease. A hallmark of many age-related diseases is the dysfunction in protein homeostasis (proteostasis), leading to the accumulation of protein aggregates. In healthy cells, a complex proteostasis network, comprising molecular chaperones and proteolytic machineries and their regulators, operates to ensure the maintenance of proteostasis. These factors coordinate protein synthesis with polypeptide folding, the conservation of protein conformation and protein degradation. However, sustaining proteome balance is a challenging task in the face of various external and endogenous stresses that accumulate during ageing. These stresses lead to the decline of proteostasis network capacity and proteome integrity. The resulting accumulation of misfolded and aggregated proteins affects, in particular, postmitotic cell types such as neurons, manifesting in disease. Recent analyses of proteome-wide changes that occur during ageing inform strategies to improve proteostasis. The possibilities of pharmacological augmentation of the capacity of proteostasis networks hold great promise for delaying the onset of age-related pathologies associated with proteome deterioration and for extending healthspan. Misfolded proteins have a high propensity to form potentially toxic aggregates. Cells employ a complex network of processes, involving chaperones and proteolytic machineries that ensure proper protein folding and remodel or degrade misfolded species and aggregates. This proteostasis network declines with age, which can be linked to human degenerative diseases.

705 citations

Journal ArticleDOI
TL;DR: BioID uses proximity-dependent biotin identification to interrogate the interactome of detergent-insoluble TDP-43 aggregates and finds them enriched for components of the nuclear pore complex and nucleocytoplasmic transport machinery.
Abstract: The cytoplasmic mislocalization and aggregation of TAR DNA-binding protein-43 (TDP-43) is a common histopathological hallmark of the amyotrophic lateral sclerosis and frontotemporal dementia disease spectrum (ALS/FTD). However, the composition of aggregates and their contribution to the disease process remain unknown. Here we used proximity-dependent biotin identification (BioID) to interrogate the interactome of detergent-insoluble TDP-43 aggregates and found them enriched for components of the nuclear pore complex and nucleocytoplasmic transport machinery. Aggregated and disease-linked mutant TDP-43 triggered the sequestration and/or mislocalization of nucleoporins and transport factors, and interfered with nuclear protein import and RNA export in mouse primary cortical neurons, human fibroblasts and induced pluripotent stem cell-derived neurons. Nuclear pore pathology is present in brain tissue in cases of sporadic ALS and those involving genetic mutations in TARDBP and C9orf72. Our data strongly implicate TDP-43-mediated nucleocytoplasmic transport defects as a common disease mechanism in ALS/FTD.

347 citations

Journal ArticleDOI
17 Apr 2019-Neuron
TL;DR: It is shown that TDP-43 at its endogenous level undergoes liquid-liquid phase separation (LLPS) within nuclei in multiple cell types and identifies a neuronal cell death mechanism that can be initiated by transient-stress-induced cytosolic de-mixing of T DP-43.

282 citations

Journal ArticleDOI
03 May 2018-Cell
TL;DR: It is demonstrated that inhibiting stress granule assembly, such as by knocking down Ataxin-2, suppresses nucleocytoplasmic transport defects as well as neurodegeneration in C9ORF72-mediated ALS/FTD.

260 citations