Hallmarks of neurodegenerative diseases

Cell, Год журнала: 2023, Номер 186(4), С. 693 - 714

Опубликована: Фев. 1, 2023

Summary

Decades of research have identified genetic factors and biochemical pathways involved in neurodegenerative diseases (NDDs). We present evidence for the following eight hallmarks NDD: pathological protein aggregation, synaptic neuronal network dysfunction, aberrant proteostasis, cytoskeletal abnormalities, altered energy homeostasis, DNA RNA defects, inflammation, cell death. describe hallmarks, their biomarkers, interactions as a framework to study NDDs using holistic approach. The can serve basis defining pathogenic mechanisms, categorizing different based on primary stratifying patients within specific NDD, designing multi-targeted, personalized therapies effectively halt NDDs.

Язык: Английский

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Amyotrophic lateral sclerosis: a clinical review

European Journal of Neurology, Год журнала: 2020, Номер 27(10), С. 1918 - 1929

Опубликована: Июнь 11, 2020

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder affecting primarily the motor system, but in which extra-motor manifestations are increasingly recognized. The loss of upper and lower neurons cortex, brain stem nuclei anterior horn spinal cord gives rise to progressive muscle weakness wasting. ALS often has focal onset subsequently spreads different body regions, where failure respiratory muscles typically limits survival 2-5 years after disease onset. In up 50% cases, there such as changes behaviour, executive dysfunction language problems. 10%-15% patients, these problems severe enough meet clinical criteria frontotemporal dementia (FTD). 10% family history suggests an autosomal dominant inheritance pattern. remaining 90% have no affected members classified sporadic ALS. causes appear be heterogeneous only partially understood. To date, more than 20 genes been associated with most common genetic cause hexanucleotide repeat expansion C9orf72 gene, responsible for 30%-50% familial 7% These expansions also frequent dementia, emphasizing molecular overlap between FTD. this day cure or effective treatment cornerstone remains multidisciplinary care, including nutritional support symptom management. review, aspects discussed, epidemiology, aetiology, pathogenesis, features, differential diagnosis, investigations, future prospects.

Язык: Английский

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Molecular Mechanisms of TDP-43 Misfolding and Pathology in Amyotrophic Lateral Sclerosis

Frontiers in Molecular Neuroscience, Год журнала: 2019, Номер 12

Опубликована: Фев. 14, 2019

TAR DNA binding protein 43 (TDP-43) is a versatile RNA/DNA involved in RNA-related metabolism. Hyper-phosphorylated and ubiquitinated TDP-43 deposits as inclusion bodies the brain spinal cord of patients with motor neuron diseases: amyotrophic lateral sclerosis (ALS) frontotemporal lobar degeneration (FTLD). While majority ALS cases (90-95%) are sporadic (sALS), among familial 5-10% involve inheritance mutations TARDBP gene remaining due to other genes such as: C9ORF72, SOD1, FUS, NEK1 etc. Strikingly however, (up 97%) also contain deposited neuronal inclusions, which suggests its pivotal role pathology. Thus, unravelling molecular mechanisms pathology, seems central therapeutics, hence, we comprehensively review current understanding TDP-43's pathology ALS. We discuss roles mutations, cytoplasmic mis-localization aberrant post-translational modifications Also, evaluate amyloid-like vitro aggregation, physiological versus pathological oligomerization vivo, liquid-liquid phase separation (LLPS), potential prion-like propagation propensity inclusions. Finally, describe various evolving TDP-43-induced toxicity impairment endocytosis mitotoxicity emerging strategies towards disaggregation therapeutics.

Язык: Английский

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Stress granules and neurodegeneration

Nature reviews. Neuroscience, Год журнала: 2019, Номер 20(11), С. 649 - 666

Опубликована: Окт. 3, 2019

Язык: Английский

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Amyotrophic lateral sclerosis

The Lancet, Год журнала: 2022, Номер 400(10360), С. 1363 - 1380

Опубликована: Сен. 15, 2022

Язык: Английский

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ALS-implicated protein TDP-43 sustains levels of STMN2, a mediator of motor neuron growth and repair

Nature Neuroscience, Год журнала: 2019, Номер 22(2), С. 167 - 179

Опубликована: Янв. 3, 2019

Язык: Английский

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RNA Granules Hitchhike on Lysosomes for Long-Distance Transport, Using Annexin A11 as a Molecular Tether

Cell, Год журнала: 2019, Номер 179(1), С. 147 - 164.e20

Опубликована: Сен. 1, 2019

Long-distance RNA transport enables local protein synthesis at metabolically-active sites distant from the nucleus. This process ensures an appropriate spatial organization of proteins, vital to polarized cells such as neurons. Here, we present a mechanism for in which granules "hitchhike" on moving lysosomes. In vitro biophysical modeling, live-cell microscopy, and unbiased proximity labeling proteomics reveal that annexin A11 (ANXA11), granule-associated phosphoinositide-binding protein, acts molecular tether between ANXA11 possesses N-terminal low complexity domain, facilitating its phase separation into membraneless granules, C-terminal membrane binding enabling interactions with granule requires ANXA11, amyotrophic lateral sclerosis (ALS)-associated mutations impair by disrupting their Thus, mediates neuronal tethering actively-transported lysosomes, performing critical cellular function is disrupted ALS.

Язык: Английский

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Common and rare variant association analyses in amyotrophic lateral sclerosis identify 15 risk loci with distinct genetic architectures and neuron-specific biology

Nature Genetics, Год журнала: 2021, Номер 53(12), С. 1636 - 1648

Опубликована: Дек. 1, 2021

Abstract Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease with lifetime risk of one in 350 people and an unmet need for disease-modifying therapies. We conducted cross-ancestry genome-wide association study (GWAS) including 29,612 patients ALS 122,656 controls, which identified 15 loci. When combined 8,953 individuals whole-genome sequencing (6,538 patients, 2,415 controls) large cortex-derived expression quantitative trait locus (eQTL) dataset (MetaBrain), analyses revealed locus-specific genetic architectures we prioritized genes either through rare variants, short tandem repeats or regulatory effects. ALS-associated loci were shared multiple traits within the spectrum but distinct enrichment patterns across brain regions cell types. Of environmental lifestyle factors obtained from literature, Mendelian randomization indicated causal role high cholesterol levels. The combination all signals reveals perturbations vesicle-mediated transport autophagy provides evidence cell-autonomous initiation glutamatergic neurons.

Язык: Английский

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TDP-43 represses cryptic exon inclusion in the FTD–ALS gene UNC13A

Nature, Год журнала: 2022, Номер 603(7899), С. 124 - 130

Опубликована: Фев. 23, 2022

Abstract A hallmark pathological feature of the neurodegenerative diseases amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) is depletion RNA-binding protein TDP-43 from nucleus neurons in brain spinal cord 1 . major function as a repressor cryptic exon inclusion during RNA splicing 2–4 Single nucleotide polymorphisms UNC13A are among strongest hits associated with FTD ALS human genome-wide association studies 5,6 , but how those variants increase risk for disease unknown. Here we show that represses exon-splicing event Loss brain, neuronal cell lines motor derived induced pluripotent stem cells resulted mRNA reduced expression. The top or humans located intron harbouring exon, they face dysfunction. Together, our data provide direct functional link between one genetic factors ( variants), loss function.

Язык: Английский

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TDP-43 loss and ALS-risk SNPs drive mis-splicing and depletion of UNC13A

Nature, Год журнала: 2022, Номер 603(7899), С. 131 - 137

Опубликована: Фев. 23, 2022

Variants of UNC13A, a critical gene for synapse function, increase the risk amyotrophic lateral sclerosis and frontotemporal dementia

Язык: Английский

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