Genetic disruption of WASHC4 drives endo-lysosomal dysfunction and cognitive-movement impairments in mice and humans

Courtland, Jamie L; Bradshaw, Tyler Wa; Waitt, Greg; Soderblom, Erik J.; Ho, Tricia; Rajab, Anna; Vancini, Ricardo; Kim, Il Hwan; Soderling, Scott H.

doi:10.7554/elife.61590

Cited by 37 publications

(34 citation statements)

References 157 publications

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“…The destabilized WASH complex inhibits endolysosomal trafficking, causing clumping of endosomes. Defective endosomal traffic impacts cognition and motor neuron function, symptoms described as nonsyndromic mental retardation [22,23].…”

Section: Introduction and Historical Perspectivementioning

confidence: 99%

Small but Mighty—Exosomes, Novel Intercellular Messengers in Neurodegeneration

Kumari

Anji

2022

Biology

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Exosomes of endosomal origin are one class of extracellular vesicles that are important in intercellular communication. Exosomes are released by all cells in our body and their cargo consisting of lipids, proteins and nucleic acids has a footprint reflective of their parental origin. The exosomal cargo has the power to modulate the physiology of recipient cells in the vicinity of the releasing cells or cells at a distance. Harnessing the potential of exosomes relies upon the purity of exosome preparation. Hence, many methods for isolation have been developed and we provide a succinct summary of several methods. In spite of the seclusion imposed by the blood–brain barrier, cells in the CNS are not immune from exosomal intrusive influences. Both neurons and glia release exosomes, often in an activity-dependent manner. A brief description of exosomes released by different cells in the brain and their role in maintaining CNS homeostasis is provided. The hallmark of several neurodegenerative diseases is the accumulation of protein aggregates. Recent studies implicate exosomes’ intercellular communicator role in the spread of misfolded proteins aiding the propagation of pathology. In this review, we discuss the potential contributions made by exosomes in progression of Alzheimer’s disease, Parkinson’s disease, and amyotrophic lateral sclerosis. Understanding contributions made by exosomes in pathogenesis of neurodegeneration opens the field for employing exosomes as therapeutic agents for drug delivery to brain since exosomes do cross the blood–brain barrier.

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Section: Introduction and Historical Perspectivementioning

confidence: 99%

Small but Mighty—Exosomes, Novel Intercellular Messengers in Neurodegeneration

Kumari

Anji

2022

Biology

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“…In addition to common familial PD-linked genes, which include α-Syn, parkin, PTEN-induced putative (PINK1), protein deglycase (DJ-1), and LRRK2, 11 other transgenic models were used in a total of 38 articles to replicate PD-MCI or PDD ( Table 5 ). The genes that these models interfered with included Pitx3, dopamine transporter (DAT), mitochondrial transcription factor A (TFAM), β-synuclein (β-Syn), A2A receptors, Atp13a2, B4galnt, Ifnb, midkine (Mdk), Ndufs4, tau, and Washc4 ( Prediger et al, 2011 ; Lei et al, 2012 ; Sekiyama et al, 2012 ; Li et al, 2013 ; Moon et al, 2013 ; Schultheis et al, 2013 ; Ejlerskov et al, 2015 ; Choi et al, 2017 ; Hwang et al, 2019 ; Wu et al, 2020 ; Courtland et al, 2021 ). Rodent, NHP, and drosophila animal models based on α-Syn are currently available.…”

Section: Transgenic Experimental Modelsmentioning

confidence: 99%

Experimental Models of Cognitive Impairment for Use in Parkinson’s Disease Research: The Distance Between Reality and Ideal

Fan

Han

Zhao

et al. 2021

Front. Aging Neurosci.

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Parkinson’s disease (PD) is the second most common neurodegenerative disease. Cognitive impairment is one of the key non-motor symptoms of PD, affecting both mortality and quality of life. However, there are few experimental studies on the pathology and treatments of PD with mild cognitive impairment (PD-MCI) and PD dementia (PDD) due to the lack of representative models. To identify new strategies for developing representative models, we systematically summarized previous studies on PD-MCI and PDD and compared differences between existing models and diseases. Our initial search identified 5432 articles, of which 738 were duplicates. A total of 227 articles met our inclusion criteria and were included in the analysis. Models fell into three categories based on model design: neurotoxin-induced, transgenic, and combined. Although the neurotoxin-induced experimental model was the most common type that was used during every time period, transgenic and combined experimental models have gained significant recent attention. Unfortunately, there remains a big gap between ideal and actual experimental models. While each model has its own disadvantages, there have been tremendous advances in the development of PD models of cognitive impairment, and almost every model can verify a hypothesis about PD-MCI or PDD. Finally, our proposed strategies for developing novel models are as follows: a set of plans that integrate symptoms, biochemistry, neuroimaging, and other objective indicators to judge and identify that the novel model plays a key role in new strategies for developing representative models; novel models should simulate different clinical features of PD-MCI or PDD; inducible α-Syn overexpression and SH-SY5Y-A53T cellular models are good candidate models of PD-MCI or PDD.

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“…Here, we show a robust density gradient-based centrifugal separation of seven fractions using frozen human angular gyrus tissue from subjects with Alzheimer’s disease as well as healthy controls. The extent of separation of lower density membranous organelles was less clear than in fresh mouse brain, 15 although it is unclear whether this is a result of post-mortem tissue freezing, or the extended fractionation scheme used by these investigators. These data suggest that spatial proteomic techniques can be used to assign a high-confidence subcellular location to approximately one-third of the robustly quantified proteins in human post-mortem brain tissue, a medium-confidence location to a further 40%, and that this can be used to highlight changes in localization profiles in response to a change in a disease condition.…”

Section: Discussionmentioning

confidence: 95%

“… 13 , 14 Spatial proteomic analysis of brains from 10-month-old mice with a disease-relevant mutation in the Wash complex subunit 4 (SWIP) gene showed disruption of the Wiskott–Aldrich syndrome protein and scar homologue complex (WASH) complex resulting in altered abundance of hundreds of proteins across multiple subcellular fractions. 15 To our knowledge, these serial fractionation techniques have not been used in frozen human tissue. The use of frozen human tissue for tissue fractionation faces three major challenges, the post-mortem interval (PMI), during which proteins may leach from their usual location into the cytosol, the complexity of the tissue which harbours hundreds of cell types, and freezing, which results in membrane breakdown.…”

Section: Introductionmentioning

confidence: 99%

Proteomic characterization of post-mortem human brain tissue following ultracentrifugation-based subcellular fractionation

Kandigian

Ethier

Kitchen

et al. 2022

Brain Communications

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Proteomic characterization of human brain tissue is increasingly utilized to identify potential novel biomarker and drug targets for a variety of neurological diseases. In whole tissue studies, results may be driven by changes in the proportion of the largest and most abundant organelles or tissue cell-type composition. Spatial proteomics approaches enhance our knowledge of disease mechanisms and changing signaling pathways at the subcellular level by taking into account the importance of cellular localization, which critically influences protein function. Density gradient-based ultracentrifugation methods allow for subcellular fractionation and have been utilized in cell lines, mouse, and human brain tissue to quantify thousands of proteins in specific enriched organelles such as the pre- and post-synapse. Serial ultra-centrifugation methods allow for the analysis of multiple cellular organelles from the same biological sample, and to our knowledge have not been previously applied to frozen post-mortem human brain tissue. The use of frozen human tissue for tissue fractionation faces two major challenges, the post-mortem interval, during which proteins may leach from their usual location into the cytosol, and freezing, which results in membrane breakdown. Despite these challenges, in this proof-of-concept study, we show that the majority of proteins segregate reproducibly into crude density-based centrifugation fractions, that the fractions are enriched for the appropriate organellar markers, and that significant differences in protein localization can be observed between tissue from individuals with Alzheimer’s Disease and control individuals.

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Genetic disruption of WASHC4 drives endo-lysosomal dysfunction and cognitive-movement impairments in mice and humans

Cited by 37 publications

References 157 publications

Small but Mighty—Exosomes, Novel Intercellular Messengers in Neurodegeneration

Small but Mighty—Exosomes, Novel Intercellular Messengers in Neurodegeneration

Experimental Models of Cognitive Impairment for Use in Parkinson’s Disease Research: The Distance Between Reality and Ideal

Proteomic characterization of post-mortem human brain tissue following ultracentrifugation-based subcellular fractionation

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