Towards an integrated approach for understanding glia in Amyotrophic Lateral Sclerosis DOI Creative Commons

Stanisław Majewski,

Pierre Klein, Séverine Boillée

et al.

Glia, Journal Year: 2024, Volume and Issue: unknown

Published: Sept. 25, 2024

Abstract Substantial advances in technology are permitting a high resolution understanding of the salience glia, and have helped us to transcend decades predominantly neuron‐centric research. In particular, recent ‘omic’ technologies enabled unique insights into glial biology, shedding light on cellular molecular aspects neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS). Here, we review studies using omic techniques attempt understand role glia ALS across different model systems post mortem tissue. We also address caveats that should be considered when interpreting such studies, how some these may mitigated through either multi‐omic approach and/or careful low throughput, fidelity orthogonal validation with particular emphasis functional validation. Finally, consider emerging their potential relevance deepening our ALS.

Language: Английский

KIF5A regulates axonal repair and time-dependent axonal transport of SFPQ granules and mitochondria in human motor neurons DOI Creative Commons
Irune Guerra San Juan, Jessie Brunner, Kevin Eggan

et al.

Neurobiology of Disease, Journal Year: 2024, Volume and Issue: unknown, P. 106759 - 106759

Published: Dec. 1, 2024

Mutations in the microtubule-binding motor protein kinesin 5 A (KIF5A) are impacted several adult-onset neuron diseases, including Amyotrophic Lateral Sclerosis, Spastic Paraplegia Type 10 and Charcot-Marie-Tooth Disease 2. While KIF5 family members transport a variety of cargos along axons, specific affected by KIF5A mutations remain poorly understood. Here, we generated null mutant human neurons analyzed impact on axonal outgrowth regeneration vitro. deficiency caused reduced neurite complexity young (DIV14) defects regeneration. did not affect neurofilament but impaired mitochondrial motility anterograde speed at DIV42. Notably, strongly splicing factor proline/glutamine-rich (SFPQ)-associated RNA granules DIV42 axons. Hence, plays critical role promoting regrowth after injury driving mitochondria especially SFPQ-associated mature neurons.

Language: Английский

Citations

1
ALS molecular subtypes are a combination of cellular, genetic, and pathological features learned by deep multiomics classifiers DOI
Kathryn O’Neill,

Regina Shaw,

Isobel Bolger

et al.

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2024, Volume and Issue: unknown

Published: July 20, 2024

Abstract Amyotrophic Lateral Sclerosis (ALS) is a complex syndrome with multiple genetic causes and wide variation in disease presentation. Despite this general heterogeneity, several common factors have been identified. For example, nearly all patients show pathological accumulations of phosphorylated TDP-43 protein affected regions the motor cortex spinal cord. Moreover, large patient cohort studies revealed that most samples can be grouped into small number ALS subtypes, as defined by their transcriptomic profiles. These molecular subtypes whether postmortem display signatures of: mitochondrial dysfunction oxidative stress (ALS-Ox), microglial activation neuroinflammation (ALS-Glia), or dense pathology associated transposable element de-silencing (ALS-TE). In study, we built deep layer neural network classifier (DANcer) has learned to accurately assign these which run on either bulk single-cell datasets. Upon applying an expanded from NYGC Consortium, Molecular Subtypes are robust across clinical centers, no new appearing quadrupled size. Signatures two strongly correlate duration: ALS-TE ALS-Glia cord, revealing correlates features. Finally, use single nucleus RNA sequencing reveal cell type-specific contributions subtype, determined our (scDANCer). Single-cell transcriptomes recapitulated neurons glia, both ALS-wide shared alterations each type well subtype-specific alterations. summary, subtypes: (1) cohorts sporadic familial samples, (2) represent combination cellular, genetic, features, (3) features ALS. Figure 0: Graphical - multiomics classifiers.

Language: Английский

Citations

0
Single-cell spatial transcriptomics reveals molecular patterns of selective neuronal vulnerability to α-synuclein pathology in a transgenic mouse model of Lewy body disease DOI Creative Commons
Liam Horan-Portelance, Michiyo Iba, Dominic J. Acri

et al.

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2024, Volume and Issue: unknown

Published: Aug. 1, 2024

One of the unifying pathological hallmarks Parkinson's disease (PD) and dementia with Lewy bodies (DLB) is presence misfolded, aggregated, often phosphorylated forms protein α-synuclein in neurons. α-Synuclein pathology appears select populations neurons throughout various cortical subcortical regions, little currently known about why some develop while others are spared. Here, we utilized subcellular-resolution imaging-based spatial transcriptomics (IST) a transgenic mouse model that overexpresses wild-type human (α-syn-tg) to evaluate patterns selective neuronal vulnerability pathology. By performing post-IST immunofluorescence for at Ser129 (pSyn), identified cell types cortex hippocampus were vulnerable or resistant developing pSyn Next, investigated transcriptional underpinnings observed using set custom probes detect genes involved processing toxicity. We expression kinase:substrate pair Plk2 , which phosphorylates Ser129, SNCA ( hSNCA ), as underlying Finally, performed differential gene analysis, comparing non-transgenic cells pSyn- pSyn+ α-syn- tg reveal changes downstream overexpression pathology, included pSyn-dependent alterations mitochondrial endolysosomal genes. This study provides comprehensive use case IST, yielding new biological insights into formation its effects PD/DLB model.

Language: Английский

Citations

0
Molecular pathology, developmental changes and synaptic dysfunction in (pre-) symptomatic human C9ORF72-ALS/FTD cerebral organoids DOI Creative Commons
Astrid T. van der Geest,

Channa E Jakobs,

Tijana Ljubikj

et al.

Acta Neuropathologica Communications, Journal Year: 2024, Volume and Issue: 12(1)

Published: Sept. 18, 2024

A hexanucleotide repeat expansion (HRE) in C9ORF72 is the most common genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Human brain imaging experimental studies indicate early changes structure connectivity C9-ALS/FTD, even before symptom onset. Because these disease phenotypes remain incompletely understood, we generated iPSC-derived cerebral organoid models from C9-ALS/FTD patients, presymptomatic C9ORF72-HRE (C9-HRE) carriers, controls. Our work revealed presence all three C9-HRE-related molecular pathologies developmental stage-dependent size organoids patients. In addition, single-cell RNA sequencing identified cell type abundance distribution organoids, including a reduction number deep layer cortical neurons neural progenitors. Further, cellular analyses patch-clamp electrophysiology detected various synapse function. Intriguingly, C9-HRE carriers displayed pathology, whereas extent to which more downstream defects, as found models, were varied for different cases. Together, results unveil 3D human tissue organization synaptic that likely constitute initial crucial understanding onset design therapeutic strategies.

Language: Английский

Citations

0
Towards an integrated approach for understanding glia in Amyotrophic Lateral Sclerosis DOI Creative Commons

Stanisław Majewski,

Pierre Klein, Séverine Boillée

et al.

Glia, Journal Year: 2024, Volume and Issue: unknown

Published: Sept. 25, 2024

Abstract Substantial advances in technology are permitting a high resolution understanding of the salience glia, and have helped us to transcend decades predominantly neuron‐centric research. In particular, recent ‘omic’ technologies enabled unique insights into glial biology, shedding light on cellular molecular aspects neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS). Here, we review studies using omic techniques attempt understand role glia ALS across different model systems post mortem tissue. We also address caveats that should be considered when interpreting such studies, how some these may mitigated through either multi‐omic approach and/or careful low throughput, fidelity orthogonal validation with particular emphasis functional validation. Finally, consider emerging their potential relevance deepening our ALS.

Language: Английский

Citations

0