Protein interaction networks in neurodegenerative diseases: From physiological function to aggregation

Journal of Biological Chemistry, Год журнала: 2022, Номер 298(7), С. 102062 - 102062

Опубликована: Май 25, 2022

The accumulation of protein inclusions is linked to many neurodegenerative diseases that typically develop in older individuals, due a combination genetic and environmental factors. In rare familial disorders, genes encoding for aggregation-prone proteins are often mutated. While the underlying mechanism leading these still remains be fully elucidated, efforts past 20 years revealed vast network protein–protein interactions play major role regulating aggregation key associated with neurodegeneration. Misfolded can oligomerize form insoluble aggregates associate molecular chaperones other elements proteolytic machineries frontline workers attempting protect cells by promoting clearance preventing aggregation. Proteins normally bound become sequestered mislocalized inclusions, their loss function. contrast, mutations, posttranslational modifications, or misfolding lead gain function inducing novel altered interactions, which turn impact numerous essential cellular processes organelles, such as vesicle trafficking mitochondria. This review examines our current knowledge involving several Alzheimer's disease, Parkinson's Huntington's amyotrophic lateral sclerosis. We aim provide an overview interaction networks central driving mitigating inclusion formation, while highlighting some proteomic studies helped uncover extent networks. Neurodegenerative (NDs) complex multifactorial pathology, result progressive damage neuronal connectivity, ultimately impaired mobility and/or cognition. Protein oligomerization gives rise extracellular intracellular common hallmark NDs. 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Язык: Английский

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Therapeutic reversal of Huntington’s disease by in vivo self-assembled siRNAs

Brain, Год журнала: 2021, Номер 144(11), С. 3421 - 3435

Опубликована: Сен. 23, 2021

Abstract Huntington’s disease is an autosomal-dominant neurodegenerative caused by CAG expansion in exon 1 of the huntingtin (HTT) gene. Since mutant (mHTT) protein root cause disease, oligonucleotide-based therapeutic approaches using small interfering RNAs (siRNAs) and antisense oligonucleotides designed to specifically silence mHTT may be novel strategies for disease. Unfortunately, lack effective vivo delivery system remains a major obstacle realizing full potential oligonucleotide therapeutics, especially regarding cortex striatum, most severely affected brain regions In this study, we present synthetic biology strategy that integrates naturally existing exosome-circulating with artificial genetic circuits self-assembly mHTT-silencing siRNA striatum. We cytomegalovirus promoter-directed circuit encoding both neuron-targeting rabies virus glycoprotein tag siRNA. After being taken up mouse livers after intravenous injection, was able reprogramme hepatocytes transcribe self-assemble into glycoprotein-tagged exosomes. The further delivered through guided Consequently, three models treated circuit, levels toxic aggregates were successfully reduced therefore ameliorating behavioural deficits striatal cortical neuropathologies. Overall, our findings establish convenient, safe siRNAs provide significant benefit

Язык: Английский

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TGF-β as a Key Modulator of Astrocyte Reactivity: Disease Relevance and Therapeutic Implications

Biomedicines, Год журнала: 2022, Номер 10(5), С. 1206 - 1206

Опубликована: Май 23, 2022

Astrocytes are essential for normal brain development and functioning. They respond to injury disease through a process referred as reactive astrogliosis, where the reactivity is highly heterogenous context-dependent. Reactive astrocytes active contributors pathology can exert beneficial, detrimental, or mixed effects following insults. Transforming growth factor-β (TGF-β) has been identified one of key factors regulating astrocyte reactivity. The genetic pharmacological manipulation TGF-β signaling pathway in animal models central nervous system (CNS) alters pathological functional outcomes. This review aims provide recent understanding regarding injury, aging, neurodegeneration. Further, it explores how modulates function context CNS injury.

Язык: Английский

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Neuroinflammation in Huntington’s Disease: A Starring Role for Astrocyte and Microglia

Current Neuropharmacology, Год журнала: 2021, Номер 20(6), С. 1116 - 1143

Опубликована: Дек. 2, 2021

Huntington's disease (HD) is a neurodegenerative genetic disorder caused by CAG repeat expansion in the huntingtin gene. HD causes motor, cognitive, and behavioral dysfunction. Since no existing treatment affects course of this disease, new treatments are needed. Inflammation frequently observed patients before symptom onset. Neuroinflammation, characterized presence reactive microglia, astrocytes inflammatory factors within brain, also detected early. However, comparison to other diseases, role neuroinflammation much less known. Work has been dedicated altered microglial astrocytic functions context HD, but attention given glial participation neuroinflammation. This review describes evidence inflammation animal models. It discusses recent knowledge on highlighting astrocyte microglia involvement considering anti-inflammatory therapeutic approaches.

Язык: Английский

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FAN1 controls mismatch repair complex assembly via MLH1 retention to stabilize CAG repeat expansion in Huntington’s disease

Cell Reports, Год журнала: 2021, Номер 36(9), С. 109649 - 109649

Опубликована: Авг. 1, 2021

CAG repeat expansion in the HTT gene drives Huntington's disease (HD) pathogenesis and is modulated by DNA damage repair pathways. In this context, interaction between FAN1, a DNA-structure-specific nuclease, MLH1, member of mismatch pathway (MMR), not defined. Here, we identify highly conserved SPYF motif at N terminus FAN1 that binds to MLH1. Our data support model where has two distinct functions stabilize repeats. On one hand, it MLH1 restrict its recruitment MSH3, thus inhibiting assembly functional MMR complex would otherwise promote expansion. other promotes accurate via nuclease activity. These highlight potential avenue for HD therapeutics attenuating somatic

Язык: Английский

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