Expression of ALS-PFN1 impairs vesicular degradation in iPSC-derived microglia

Nature Communications, Journal Year: 2024, Volume and Issue: 15(1)

Published: March 20, 2024

Abstract Microglia play a pivotal role in neurodegenerative disease pathogenesis, but the mechanisms underlying microglia dysfunction and toxicity remain to be elucidated. To investigate effect of disease-linked genes on intrinsic properties microglia, we studied microglia-like cells derived from human induced pluripotent stem (iPSCs), termed iMGs, harboring mutations profilin-1 (PFN1) that are causative for amyotrophic lateral sclerosis (ALS). ALS-PFN1 iMGs exhibited evidence lipid dysmetabolism, autophagy dysregulation deficient phagocytosis, canonical function. Mutant PFN1 also displayed enhanced binding affinity PI3P, critical signaling molecule involved autophagic endocytic processing. Our cumulative data implicate gain-of-toxic function mutant within endo-lysosomal pathways, as administration rapamycin rescued phagocytic iMGs. These outcomes demonstrate utility research microglial vesicular degradation pathways pathogenesis these disorders.

Language: Английский

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The toxic metal hypothesis for neurological disorders

Frontiers in Neurology, Journal Year: 2023, Volume and Issue: 14

Published: June 23, 2023

Multiple sclerosis and the major sporadic neurogenerative disorders, amyotrophic lateral sclerosis, Parkinson disease, Alzheimer disease are considered to have both genetic environmental components. Advances been made in finding predispositions these but it has difficult pin down agents that trigger them. Environmental toxic metals implicated neurological since human exposure is common from anthropogenic natural sources, damaging properties suspected underlie many of disorders. Questions remain, however, as how enter nervous system, if one or combinations sufficient precipitate metal results different patterns neuronal white matter loss. The hypothesis presented here damage selective locus ceruleus neurons causes dysfunction blood-brain barrier. This allows circulating toxicants astrocytes, where they transferred to, damage, oligodendrocytes, neurons. type disorder arises depends on (i) which damaged, (ii) variants give rise susceptibility uptake, cytotoxicity, clearance, (iii) age, frequency, duration toxicant exposure, (iv) uptake various mixtures metals. Evidence supporting this presented, concentrating studies examined distribution system. Clinicopathological features shared between disorders listed can be linked Details provided applies multiple neurodegenerative Further avenues explore for suggested. In conclusion, may play a part several While further evidence support needed, protect system would prudent take steps reduce pollution industrial, mining, manufacturing burning fossil fuels.

Language: Английский

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The endolysosomal pathway and ALS/FTD

Trends in Neurosciences, Journal Year: 2023, Volume and Issue: 46(12), P. 1025 - 1041

Published: Oct. 10, 2023

Language: Английский

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How villains are made: The translation of dipeptide repeat proteins in C9ORF72-ALS/FTD

Gene, Journal Year: 2023, Volume and Issue: 858, P. 147167 - 147167

Published: Jan. 5, 2023

Language: Английский

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The Inflammatory Puzzle: Piecing together the Links between Neuroinflammation and Amyotrophic Lateral Sclerosis

Aging and Disease, Journal Year: 2023, Volume and Issue: 15(1), P. 96 - 96

Published: May 23, 2023

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease that has complex genetic basis. Through advancements in screening, researchers have identified more than 40 mutant genes associated with ALS, some of which impact immune function. Neuroinflammation, abnormal activation cells and excessive production inflammatory cytokines the central nervous system, significantly contributes to pathophysiology ALS. In this review, we examine recent evidence on involvement ALS-associated dysregulation, specific focus cyclic GMP-AMP synthase (cGAS)-stimulator interferon (STING) signaling pathway N6-methyladenosine (m

Language: Английский

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A toxic gain-of-function mechanism in C9orf72 ALS impairs the autophagy-lysosome pathway in neurons

Acta Neuropathologica Communications, Journal Year: 2023, Volume and Issue: 11(1)

Published: Sept. 18, 2023

Abstract Background Motor neurons (MNs), which are primarily affected in amyotrophic lateral sclerosis (ALS), a specialized type of that long and non-dividing. Given their unique structure, these cells heavily rely on transport organelles along axons the process autophagy to maintain cellular homeostasis. It has been shown disruption pathway is sufficient cause progressive neurodegeneration defects have associated with various subtypes ALS, including those caused by hexanucleotide repeat expansions C9orf72 gene. A more comprehensive understanding dysfunctional mechanisms will help rationalize design potent selective therapies for -ALS. Methods In this study, we used induced pluripotent stem cell (iPSC)-derived MNs from -ALS patients isogenic control lines identify underlying causing dysregulations autophagy-lysosome pathway. Additionally, ascertain potential impact loss-of-function autophagic defects, characterized observed phenotypes knockout iPSC line (C9-KO). Results Despite evident presence dysfunctions several aspects pathway, such as disrupted lysosomal homeostasis, abnormal lysosome morphology, inhibition flux, accumulation p62 MNs, were surprised find had minimal influence phenotypes. Instead, impairment endosome maturation result loss-of-function. our study shed light pathological -ALS, detected an increased TBK1 phosphorylation at S172 derived ALS patients. Conclusions Our data provides further insight into involvement strongly indicate mainly due toxic gain-of-function

Language: Английский

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Two-sample Mendelian randomization analysis of 91 circulating inflammatory protein levels and amyotrophic lateral sclerosis

Frontiers in Aging Neuroscience, Journal Year: 2024, Volume and Issue: 16

Published: March 27, 2024

Introduction Amyotrophic Lateral Sclerosis (ALS) is a neurodegenerative disease with poorly understood pathophysiology. Recent studies have highlighted systemic inflammation, especially the role of circulating inflammatory proteins, in ALS. Methods This study investigates potential causal link between these proteins and We employed two-sample Mendelian Randomization(MR) approach, analyzing data from large-scale genome-wide association to explore relationship 91 included various MR methods like Egger, weighted median, inverse-variance weighted, complemented by sensitivity analyses for robust results. Results Significant associations were observed levels including Adenosine Deaminase, Interleukin-17C, Oncostatin-M, Leukemia Inhibitory Factor Receptor, Osteoprotegerin, ALS risk. Consistencies noted across different P -value thresholds. Bidirectional suggested that risk might influence certain proteins. Discussion Our findings, via analysis, indicate sheds new light on pathophysiology suggests possible therapeutic targets. Further research required confirm results understand specific roles

Language: Английский

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TDP-43 proteinopathy in frontotemporal lobar degeneration and amyotrophic lateral sclerosis: From pathomechanisms to therapeutic strategies

Ageing Research Reviews, Journal Year: 2024, Volume and Issue: 100, P. 102441 - 102441

Published: July 27, 2024

Proteostasis failure is a common pathological characteristic in neurodegenerative diseases. Revitalizing clearance systems could effectively mitigate these The transactivation response (TAR) DNA-binding protein 43 (TDP-43) plays critical role as an RNA/DNA-binding RNA metabolism and synaptic function. Accumulation of TDP-43 aggregates the central nervous system hallmark frontotemporal lobar degeneration (FTLD) amyotrophic lateral sclerosis (ALS). Autophagy, major highly conserved degradation pathway, holds potential for degrading aggregated alleviating FTLD/ALS. This review explores causes aggregation, FTLD/ALS-related genes, key autophagy factors, autophagy-based therapeutic strategies targeting proteinopathy. Understanding underlying mechanisms proteinopathy can facilitate interventions.

Language: Английский

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The role of autophagy in the pathogenesis and treatment of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD)

Autophagy Reports, Journal Year: 2025, Volume and Issue: 4(1)

Published: March 20, 2025

Language: Английский

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Decoding the genetic blueprints of neurological disorders: disease mechanisms and breakthrough gene therapies

Frontiers in Neurology, Journal Year: 2025, Volume and Issue: 16

Published: April 11, 2025

Neurological disorders pose a rapidly growing global health burden, significantly affecting cognitive and motor functions with profound societal repercussions. This comprehensive review probe into the genetic foundations of various neurological conditions while exploring innovative RNA-based therapeutics particularly gene therapies as cutting edge treatment strategies. Through an in-depth analysis existing literature, study examines landscape, disease mechanisms, gene-based intervention possibilities across range disorders, including Cerebellar Ataxias, Autosomal Recessive Ataxia, Mitochondrial Multiple System Atrophy (MSA), Idiopathic Late-Onset Hereditary Spastic Paraplegias, Alzheimer’s Disease, Vascular Dementia, Lewy Body Frontotemporal Dementias, Inherited Prion Diseases, Huntington’s Disease. It uncovers intricate network mutations driving these shedding light on their mechanisms uncovering promising therapeutic targets. The also highlights remarkable potential therapeutics, standing at forefront precision approaches. By offering up-to-date understanding intricacies emerging in this contributes to advancement medicine neurology. paves way for future research clinical applications aimed improving patient care outcomes.

Language: Английский

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