Lysosomes cell autonomously regulate myeloid cell states and immune responses DOI Open Access
Leon Tejwani, Christopher Balak,

Lukas L Skuja

и другие.

bioRxiv (Cold Spring Harbor Laboratory), Год журнала: 2024, Номер unknown

Опубликована: Ноя. 13, 2024

ABSTRACT Myeloid cells maintain tissue homeostasis via the recognition, engulfment, and lysosomal clearance of dying cellular debris, which is often accompanied by changes from homeostatic to reactive states. While a role for phagocytic receptors in gating these transitions has been described 1,2 , less known about if how lysosomes can contribute transcriptional functional plasticity. To determine health impacts myeloid cell states, we evaluated microglia macrophages deficient progranulin (encoded Grn ), protein with pleiotropic functions whose loss associated several neurodegenerative diseases 3–8 . Single-cell RNA-sequencing aged mouse brain identified knockout (KO)-specific microglial subpopulation marked high GPNMB expression that displays hallmarks dysfunction, including lipofuscin accumulation. Epigenetic analysis revealed MITF/TFE transcription factors as key mediators states deficiency. In addition identifying core response diverse stressors, targeted perturbations various properties vitro uncovered autonomous, TREM2- independent, deacidification (via v-ATPase or VPS34 function) overlaps KO phenotypes, induction gene program, increased proliferation, secretion pro-inflammatory cytokines. Compound loss-of-function approaches established upregulation upon stress required compensatory enhance function promoting acidification. Finally, pharmacological endolysosomal reacidification through sodium/proton exchanger inhibition partially rescued phenotypes. Overall, data establish fundamental link between epigenetic, transcriptional, observed neurodegeneration models.

Язык: Английский

Neurological Emergency Treatment Strategy: A Neuron-Targeted Regulation System for Reactive Oxygen Species Metabolism through Ferroptosis Modulation DOI

Yibo Ying,

Xiong Cai,

Peng Dai

и другие.

ACS Nano, Год журнала: 2025, Номер unknown

Опубликована: Фев. 25, 2025

Spinal cord injury (SCI) represents a significant clinical challenge. Following SCI, the implementation of protective measures for neurons is critically important. Current applications hormone pulse therapy exhibit variable efficacy and considerable side effects, highlighting an urgent need therapeutic strategies. This study investigates pathological conditions ischemia hypoxia in SCI region, complemented by early transcriptome sequencing postinjury. Our findings suggest that targeting ferroptosis pivotal neuroprotection following SCI. Aiming at cascade effect mitochondrial damage leading to reactive oxygen species (ROS) production, along with extensive ROS-mediated lysosomal during signaling, we developed liposome-based system regulating iron metabolism─DTLS@CAT. innovative liposome designed specifically target neuronal mitochondria, effectively eliminate mitoROS, modulate complex interactions among metabolism, lysosomes, ROS facilitate recovery from

Язык: Английский

Процитировано

0
Commander complex regulates lysosomal function and is implicated in Parkinson’s disease risk DOI
Georgia Minakaki, Nathaniel Safren, Bernabé I. Bustos

и другие.

Science, Год журнала: 2025, Номер 388(6743), С. 204 - 211

Опубликована: Апрель 10, 2025

Variants in GBA1 resulting decreased lysosomal glucocerebrosidase (GCase) activity are a common risk factor for Parkinson’s disease (PD) and dementia with Lewy bodies (DLB). Incomplete penetrance of variants suggests that additional genes contribute to PD DLB manifestation. By using pooled genome-wide CRISPR interference screen, we identified copper metabolism MURR1 domain–containing 3 (COMMD3) protein, component the COMMD/coiled-coil protein 22 (CCDC22)/CCDC93 (CCC) Commander complexes, as modifier GCase activity. Loss COMMD3 increased release proteins through extracellular vesicles, leading their impaired delivery endolysosomes consequent dysfunction. Rare gene family were associated risk. Thus, COMMD related complexes regulate homeostasis may represent modifiers other neurodegenerative diseases

Язык: Английский

Процитировано

0
LATE-NC Stage 3: a diagnostic rubric to differentiate severe LATE-NC from FTLD-TDP DOI Creative Commons
Ryan K. Shahidehpour, Yuriko Katsumata, Dennis W. Dickson

и другие.

Acta Neuropathologica, Год журнала: 2025, Номер 149(1)

Опубликована: Апрель 28, 2025

A diagnostic rubric is required to distinguish between limbic-predominant age-related TDP-43 encephalopathy neuropathologic change (LATE-NC) and frontotemporal lobar degeneration with inclusions (FTLD-TDP). In LATE-NC Stage 3, proteinopathy present in the middle frontal gyrus (MFG), thus posing a potential challenge differentiating these severe cases from FTLD-TDP. 3 other proteinopathies were analyzed University of Kentucky (total n = 514 pathology assessed), The 90+ Study at California Irvine (n 458), Mayo Clinic 5067) brain banks. Digital was used quantify burden select subset 51), complemented by previously-described manual counting method expert examinations evaluate qualitative features such as FTLD-TDP types subtypes neuronal cytoplasmic (NCIs). To clinical genetic characteristics data National Alzheimer's Coordinating Center (NACC) Neuropathology Data set correlated findings Disease Genetics Consortium (ADGC). When using quantification MFG criterion, more than 90% could be classified either or Diagnostically challenging scenarios included Type B relatively mild novel non-LATE-NC, non-FTLD-TDP pathologic subtype pathology. Taking pitfalls into account, classification schema developed that correctly diagnose all cases. There no difference disease pathological load Stages 2 versus 3. analyses, GRN (rs5848) risk allele preferentially associated whereas TMEM106B APOE risk-associated variants not. conclusion, differentiated reliably TDP-43-opathies, based on data-driven rubric.

Язык: Английский

Процитировано

0
PGRN as an emerging regulator of lipid metabolism in neurodegenerative diseases DOI Creative Commons
Yixin Shi,

Wenyu Hou,

B.-M. Li

и другие.

Communications Biology, Год журнала: 2025, Номер 8(1)

Опубликована: Июнь 2, 2025

Dysregulated lipid metabolism in microglia represents a hallmark of neuroinflammation and is often observed variety neurodegenerative diseases. The exact molecular mechanisms underlying the induction altered homeostasis how it contributes to neurodegeneration remain be deciphered. Progranulin (PGRN) lysosomal glycoprotein encoded by GRN. Loss-of-function mutations or variants GRN have been linked various PGRN has recently identified as regulator droplet formation microglia. Additionally, reported interact with molecules modulate metabolism, including glycerolipids sphingolipids neurons. Hence, deficiency-mediated dysregulation may represent significant contributing factor pathogenesis related Understanding regulates crucial for developing therapeutic strategies restore mitigate neuroinflammation, thus offering hope effective treatments combat these disorders future.

Язык: Английский

Процитировано

0
Lysosomes cell autonomously regulate myeloid cell states and immune responses DOI Open Access
Leon Tejwani, Christopher Balak,

Lukas L Skuja

и другие.

bioRxiv (Cold Spring Harbor Laboratory), Год журнала: 2024, Номер unknown

Опубликована: Ноя. 13, 2024

ABSTRACT Myeloid cells maintain tissue homeostasis via the recognition, engulfment, and lysosomal clearance of dying cellular debris, which is often accompanied by changes from homeostatic to reactive states. While a role for phagocytic receptors in gating these transitions has been described 1,2 , less known about if how lysosomes can contribute transcriptional functional plasticity. To determine health impacts myeloid cell states, we evaluated microglia macrophages deficient progranulin (encoded Grn ), protein with pleiotropic functions whose loss associated several neurodegenerative diseases 3–8 . Single-cell RNA-sequencing aged mouse brain identified knockout (KO)-specific microglial subpopulation marked high GPNMB expression that displays hallmarks dysfunction, including lipofuscin accumulation. Epigenetic analysis revealed MITF/TFE transcription factors as key mediators states deficiency. In addition identifying core response diverse stressors, targeted perturbations various properties vitro uncovered autonomous, TREM2- independent, deacidification (via v-ATPase or VPS34 function) overlaps KO phenotypes, induction gene program, increased proliferation, secretion pro-inflammatory cytokines. Compound loss-of-function approaches established upregulation upon stress required compensatory enhance function promoting acidification. Finally, pharmacological endolysosomal reacidification through sodium/proton exchanger inhibition partially rescued phenotypes. Overall, data establish fundamental link between epigenetic, transcriptional, observed neurodegeneration models.

Язык: Английский

Процитировано

0