Multi-omics study reveals differential expression and phosphorylation of autophagy-related proteins in autism spectrum disorder DOI Creative Commons

Eden Deri,

Shashank Kumar Ojha,

Maryam Kartawy

et al.

Scientific Reports, Journal Year: 2025, Volume and Issue: 15(1)

Published: March 29, 2025

Our multi-omics study investigated the molecular mechanisms underlying autism spectrum disorder (ASD) using Shank3Δ4–22 and Cntnap2−/− mouse models. Through global- phospho- proteomics of cortex, we focused on shared changes found that autophagy was particularly affected in both Global identified a small number differentially expressed proteins significantly impact postsynaptic components synaptic function, including key pathways such as mTOR signaling. Phosphoproteomics revealed unique phosphorylation sites autophagy-related ULK2, RB1CC1, ATG16L1, ATG9, suggesting altered patterns contribute to impaired autophagic flux ASD. SH-SY5Y cells with SHANK3 gene deletion showed elevated LC3-II p62 levels, indicating autophagosome accumulation initiation, while reduced level lysosomal activity marker LAMP1 suggested autophagosome-lysosome fusion. The highlights involvement reactive nitrogen species nitric oxide (NO) disruption. Importantly, inhibition neuronal NO synthase (nNOS) by 7-NI normalized markers levels primary cultured neurons. We have previously shown nNOS improved behavioral phenotypes reveals differential expression ASD but further investigation is needed prove full underscores need for examination into functional consequences sites, which may offer potential novel therapeutic targets treatment.

Language: Английский

Shared genetic risk loci between Alzheimer’s disease and related dementias, Parkinson’s disease, and amyotrophic lateral sclerosis DOI Creative Commons
Michael Wainberg, Shea J. Andrews, Shreejoy J. Tripathy

et al.

Alzheimer s Research & Therapy, Journal Year: 2023, Volume and Issue: 15(1)

Published: June 16, 2023

Genome-wide association studies (GWAS) have indicated moderate genetic overlap between Alzheimer's disease (AD) and related dementias (ADRD), Parkinson's (PD) amyotrophic lateral sclerosis (ALS), neurodegenerative disorders traditionally considered etiologically distinct. However, the specific variants loci underlying this remain almost entirely unknown.

Language: Английский

Citations

49
Neuronal Autophagy: Regulations and Implications in Health and Disease DOI Creative Commons

Caroline Liénard,

Alexandre Pintart,

Pascale Bomont

et al.

Cells, Journal Year: 2024, Volume and Issue: 13(1), P. 103 - 103

Published: Jan. 4, 2024

Autophagy is a major degradative pathway that plays key role in sustaining cell homeostasis, integrity, and physiological functions. Macroautophagy, which ensures the clearance of cytoplasmic components engulfed double-membrane autophagosome fuses with lysosomes, orchestrated by complex cascade events. has particularly strong impact on nervous system, mutations core cause numerous neurological diseases. We first review regulation autophagy, from biogenesis to lysosomal degradation associated neurodevelopmental/neurodegenerative disorders. then describe how this process specifically regulated axon somatodendritic compartment it altered In particular, we present neuronal specificities spatial control biogenesis, close relationship maturation axonal transport, synaptic activity. Finally, discuss functions autophagy during development adulthood.

Language: Английский

Citations

19
Regulation of mitophagy by the NSL complex underlies genetic risk for Parkinson’s disease at 16q11.2 and MAPT H1 loci DOI Creative Commons
Marc P. M. Soutar, Daniela Melandri, Benjamin O’Callaghan

et al.

Brain, Journal Year: 2022, Volume and Issue: 145(12), P. 4349 - 4367

Published: Sept. 8, 2022

Abstract Parkinson’s disease is a common incurable neurodegenerative disease. The identification of genetic variants via genome-wide association studies has considerably advanced our understanding the risk. Understanding functional significance risk loci now critical step towards translating these advances into an enhanced biological Impaired mitophagy key causative pathway in familial disease, but its relevance to idiopathic unclear. We used screening assay evaluate genes identified through studies. two new regulators PINK1-dependent initiation, KAT8 and KANSL1, previously shown modulate lysine acetylation. These findings suggest PINK1-mitophagy contributing factor KANSL1 located on chromosome 17q21 where associated gene long been considered be MAPT. While data do not exclude possible between MAPT they provide strong evidence that plays crucial role Finally, results enrich physiological events regulating establish novel for drug targeting neurodegeneration.

Language: Английский

Citations

49
omicSynth: An open multi-omic community resource for identifying druggable targets across neurodegenerative diseases DOI Creative Commons
Chelsea X. Alvarado, Mary B. Makarious, Cory A. Weller

et al.

The American Journal of Human Genetics, Journal Year: 2024, Volume and Issue: 111(1), P. 150 - 164

Published: Jan. 1, 2024

Treatments for neurodegenerative disorders remain rare, but recent FDA approvals, such as lecanemab and aducanumab Alzheimer disease (MIM: 607822), highlight the importance of underlying biological mechanisms in driving discovery creating modifying therapies. The global population is aging, an urgent need therapeutics that stop progression eliminate symptoms. In this study, we create open framework resource evidence-based identification therapeutic targets disease. We use summary-data-based Mendelian randomization to identify genetic drug repurposing. parallel, provide mechanistic insights into processes potential network-level consequences gene-based therapeutics. 116 disease, 3 amyotrophic lateral sclerosis 105400), 5 Lewy body dementia 127750), 46 Parkinson 605909), 9 progressive supranuclear palsy 601104) target genes passing multiple test corrections (p

Language: Английский

Citations

9
The role of chromatin-related epigenetic modulations in CAKUT DOI
Lars König, Miriam Schmidts

Current topics in developmental biology/Current Topics in Developmental Biology, Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 1, 2025

Language: Английский

Citations

1
Kansl1 haploinsufficiency impairs autophagosome-lysosome fusion and links autophagic dysfunction with Koolen-de Vries syndrome in mice DOI Creative Commons
Ting Li,

Dingyi Lu,

Chengcheng Yao

et al.

Nature Communications, Journal Year: 2022, Volume and Issue: 13(1)

Published: Feb. 17, 2022

Abstract Koolen-de Vries syndrome (KdVS) is a rare disorder caused by haploinsufficiency of KAT8 regulatory NSL complex subunit 1 ( KANSL1 ), which characterized intellectual disability, heart failure, hypotonia, and congenital malformations. To date, no effective treatment has been found for KdVS, largely due to its unknown pathogenesis. Using siRNA screening, we identified as an essential gene autophagy. Mechanistic study shows that modulates autophagosome-lysosome fusion cargo degradation via transcriptional regulation autophagosomal gene, STX17 . Kansl1 +/− mice exhibit impairment in the autophagic clearance damaged mitochondria accumulation reactive oxygen species, thereby resulting defective neuronal cardiac functions. Moreover, discovered FDA-approved drug 13-cis retinoic acid can reverse these mitophagic defects neurobehavioral abnormalities promoting fusion. Hence, findings demonstrate critical role autophagy indicate potentially viable therapeutic strategy KdVS.

Language: Английский

Citations

31
Epigenetic regulation of autophagy-related genes: Implications for neurodevelopmental disorders DOI Creative Commons
Elly Lewerissa, Nael Nadif Kasri, Katrin Linda

et al.

Autophagy, Journal Year: 2023, Volume and Issue: 20(1), P. 15 - 28

Published: Sept. 6, 2023

Macroautophagy/autophagy is an evolutionarily highly conserved catabolic process that important for the clearance of cytosolic contents to maintain cellular homeostasis and survival. Recent findings point toward a critical role autophagy in brain function, not only by preserving neuronal health, but especially controlling different aspects development functioning. In line with this, mutations autophagy-related genes are linked various key characteristics symptoms neurodevelopmental disorders (NDDs), including autism, micro-/macrocephaly, epilepsy. However, group NDDs caused relatively small. A significant proportion associated encoding epigenetic regulatory proteins modulate gene expression, so-called chromatinopathies. Intriguingly, several NDD-linked chromatinopathy have been shown regulate genes, albeit non-neuronal contexts. From these studies it becomes evident tight transcriptional regulation crucial control autophagic activity. This opens exciting possibility aberrant might underly nervous system impairments disturbed regulation. We here summarize NDD-related known genes. Thereby, we want highlight as candidate hub mechanism

Language: Английский

Citations

22
The potential of in vitro neuronal networks cultured on micro electrode arrays for biomedical research DOI Creative Commons

Marta Cerina,

Maria Carla Piastra, Monica Frega

et al.

Progress in Biomedical Engineering, Journal Year: 2023, Volume and Issue: 5(3), P. 032002 - 032002

Published: April 18, 2023

Abstract In vitro neuronal models have become an important tool to study healthy and diseased circuits. The growing interest of neuroscientists explore the dynamics systems increasing need observe, measure manipulate not only single neurons but populations cells pushed for technological advancement. this sense, micro-electrode arrays (MEAs) emerged as a promising technique, made cell culture dishes with embedded micro-electrodes allowing non-invasive relatively simple measurement activity cultures at network level. past decade, MEAs popularity has rapidly grown. MEA devices been extensively used mainly derived from rodents. Rodent on employed investigate physiological mechanisms, effect chemicals in neurotoxicity screenings, model electrophysiological phenotype networks different pathological conditions. With advancements human induced pluripotent stem (hiPSCs) technology, differentiation adult donors became possible. hiPSCs-derived develop patient-specific platforms characterize pathophysiological test drugs, paving way towards personalized medicine. review, we first describe technology information that can be obtained recordings. Then, give overview studies which combination (i.e. rodent 2D three-dimensional (3D) cultures, organotypic brain slices, 3D organoids) biomedical research, including physiology studies, disease modeling, drug testing. We end by discussing potential, challenges future perspectives providing some guidance choice device, experimental design, data analysis reporting scientific publications.

Language: Английский

Citations

20
Dendritic spine and synapse pathology in chromatin modifier-associated autism spectrum disorders and intellectual disability DOI Creative Commons

Thomas James L. Ford,

Byeong Tak Jeon,

Hyunkyoung Lee

et al.

Frontiers in Molecular Neuroscience, Journal Year: 2023, Volume and Issue: 15

Published: Jan. 19, 2023

Formation of dendritic spine and synapse is an essential final step brain wiring to establish functional communication in the developing brain. Recent findings have displayed altered morphogenesis, plasticity, related molecular mechanisms animal models post-mortem human brains autism spectrum disorders (ASD) intellectual disability (ID). Many genes proteins are shown be associated with spines development, therefore neurodevelopmental disorders. In this review, however, particular attention will given chromatin modifiers such as AT-Rich Interactive Domain 1B (ARID1B), KAT8 regulatory non-specific lethal (NSL) complex subunit 1 (KANSL1), WD Repeat 5 (WDR5) which among strong susceptibility factors for ASD ID. Emerging evidence highlights critical status these remodeling molecules morphogenesis synaptic functions. Molecular cellular insights ARID1B, KANSL1, WDR5 integrate into our current knowledge understanding interpreting pathogenesis Modulation their activities or levels may option potential therapeutic treatment strategies conditions.

Language: Английский

Citations

17
Large‐Area Field Potential Imaging Having Single Neuron Resolution Using 236 880 Electrodes CMOS‐MEA Technology DOI Creative Commons
Ikuro Suzuki, Naoki Matsuda,

Xiaobo Han

et al.

Advanced Science, Journal Year: 2023, Volume and Issue: 10(20)

Published: April 23, 2023

Abstract The electrophysiological technology having a high spatiotemporal resolution at the single‐cell level and noninvasive measurements of large areas provide insights on underlying neuronal function. Here, complementary metal‐oxide semiconductor (CMOS)‐microelectrode array (MEA) is used that uses 236 880 electrodes each with an electrode size 11.22 × µm covering wide area 5.5 5.9 mm in presenting detailed single‐cell‐level neural activity analysis platform for brain slices, human iPS cell‐derived cortical networks, peripheral neurons, organoids. Propagation pattern characteristics between regions changes synaptic propagation into compounds based time‐series patterns, classification single DRG neuron firing patterns compound responses, axonal conduction to anticancer drugs, network activities transition organoids are extracted. This using CMOS‐MEA provides new understanding basic mechanisms circuits vitro ex vivo, neurological diseases drug discovery, toxicity assessment.

Language: Английский

Citations

17