Alpha-synuclein inclusion responsive microglia are resistant to CSF1R inhibition DOI Creative Commons
Anna C. Stoll,

Christopher J. Kemp,

Joseph R. Patterson

et al.

Journal of Neuroinflammation, Journal Year: 2024, Volume and Issue: 21(1)

Published: April 25, 2024

Abstract Background Parkinson’s disease (PD) is a neurodegenerative disorder that characterized by the presence of proteinaceous alpha-synuclein (α-syn) inclusions (Lewy bodies), markers neuroinflammation and progressive loss nigrostriatal dopamine (DA) neurons. These pathological features can be recapitulated in vivo using α-syn preformed fibril (PFF) model synucleinopathy. We have previously determined microglia proximal to PFF-induced nigral increase soma size, upregulate major-histocompatibility complex-II (MHC-II) expression, expression suite inflammation-associated transcripts. This microglial response observed months prior degeneration, suggesting reacting inclusion may contribute neurodegeneration could represent potential target for novel therapeutics. The goal this study was determine whether colony stimulating factor-1 receptor (CSF1R)-mediated depletion impacts magnitude aggregation, or context PFF model. Methods Male Fischer 344 rats were injected intrastriatally with either PFFs saline. Rats continuously administered Pexidartinib (PLX3397B, 600 mg/kg), CSF1R inhibitor, deplete period 2 6 months. Results inhibition resulted significant (~ 43%) ionized calcium-binding adapter molecule 1 immunoreactive (Iba-1ir) within SNpc. However, did not impact number, number MHC-II Cd74 , Cxcl10 Rt-1a2 Grn Csf1r Tyrobp Fcer1g associated phosphorylated (pSyn) inclusions. Further, accumulation pSyn degeneration neurons impacted inhibition. Paradoxically, long term increased size remaining Iba-1ir both control rats, as well extranigral regions. Conclusions Collectively, our results suggest does viable disease-modifying strategy PD.

Language: Английский

HC070, a Transient Receptor Potential Canonical 5 (TRPC5) Channels Inhibitor Ameliorated α‐synuclein Preformed Fibrils‐Induced Parkinson's Disease: A Neurobehavioural and Mechanistic Study DOI Open Access
Bhupesh Vaidya,

Soumojit Biswas,

Ipsita Roy

et al.

Journal of Biochemical and Molecular Toxicology, Journal Year: 2025, Volume and Issue: 39(3)

Published: March 1, 2025

ABSTRACT Alpha‐synuclein pathology is a characteristic feature of Parkinson's disease (PD) and related synucleinopathies. As result, reducing alpha‐synuclein one the mechanisms being looked at for development newer agents which target these diseases. In present study, we investigated potential HC070, transient receptor canonical 5 (TRPC5) channel inhibitor in PD. TRPC5 channels are activated response to oxidative stress mediators apoptosis (calpain), processes also closely linked toxicity. Using exposure alpha synuclein‐preformed fibrils Sprague Dawley rats SH‐SY5Y cells, induced PD vitro vivo model systems. It was followed by estimation behavioural deficits, molecular parameters biochemical estimations. Results our experiments revealed that animals treated intraperitoneally with HC070 exhibited reduced levels accompanied improvement tyrosine hydroxylase levels, mitochondrial health reduction calpain signalling. Furthermore, administration caused along seen motor cognitive deficits. Similar protection observed cells exposed PFF. Overall, study demonstrates novel role inhibition reversal toxicity associated pathology.

Language: Английский

Citations

0
Intrastriatal injection of alpha-synuclein preformed fibrils to rats results in L-DOPA reversible sensorimotor impairments and alterations in non-motor function DOI Creative Commons
Sheila M. Fleming, S. Mark Scott,

Edward J. Hamad

et al.

Frontiers in Neuroscience, Journal Year: 2025, Volume and Issue: 19

Published: April 1, 2025

The alpha-synuclein (α-syn) preformed fibril (PFF) model of Parkinson's disease (PD) is widely used in rodents to understand the mechanisms contributing progression pathology and neurodegeneration disorder. While time course α-syn PFF rat has been well characterized, it more challenging determine reliable reproducible behavior impairments. This mainly due injections resulting a partial nigrostriatal lesion that make motor anomalies subtle difficult detect, just as patients with PD. In present study we sought examine effect increased striatal distribution injection quantity PFFs rats on accumulation phosphorylated inclusions, degeneration, sensorimotor behavior, nonmotor function related Male Fischer 344 were injected unilaterally striatum total 24μg distributed into three sites, or an equal volume phosphate buffered saline (PBS) control condition. Sensorimotor was assessed using battery behavioral tests sensitive varying degrees neurodegeneration. Non-motor testing included assays for olfaction, emotional reactivity, cognitive function, sleep. At six months post injection, displayed significant movement somatosensory asymmetries compared rats. Time initiate forelimb step contact adhesive stimulus forepaw took significantly longer contralateral limb ipsilateral Further, hindlimb stepping cylinder reduced PFF-injected controls. Cognitive also affected rats, investigation decreased object recognition test. Levodopa reversibility observed initiation tests. Postmortem analysis revealed 55% loss nigral tyrosine hydroxylase immunoreactive neurons 63% reduction dopamine content Thus, surgical parameters, sufficient degeneration can be achieved manifest non-motor deficits. These parameters will important preclinical assessment novel diseasemodifying therapies.

Language: Английский

Citations

0
Pathological α-synuclein dysregulates epitranscriptomic writer METTL3 to drive neuroinflammation in microglia DOI

Cameron Miller,

Alyssa Ealy,

Amanda Gregory

et al.

Cell Reports, Journal Year: 2025, Volume and Issue: 44(5), P. 115618 - 115618

Published: April 23, 2025

Language: Английский

Citations

0
Taurochenodeoxycholic acid activates autophagy and suppresses inflammatory responses in microglia of MPTP-induced Parkinson’s disease mice via AMPK/mTOR, AKT/NFκB and Pink1/Parkin signaling pathways mediated by Takeda G protein-coupled receptor 5 DOI

Chenyang Ni,

Lupeng Wang,

Yuyan Bai

et al.

Free Radical Biology and Medicine, Journal Year: 2025, Volume and Issue: unknown

Published: May 1, 2025

Language: Английский

Citations

0
The Role of Microglia and Astrocytes in the Pathomechanism of Neuroinflammation in Parkinson’s Disease—Focus on Alpha-Synuclein DOI Creative Commons
Oliwia Harackiewicz, Beata Grembecka

Journal of Integrative Neuroscience, Journal Year: 2024, Volume and Issue: 23(11)

Published: Nov. 15, 2024

Glial cells, including astrocytes and microglia, are pivotal in maintaining central nervous system (CNS) homeostasis responding to pathological insults. This review elucidates the complex immunomodulatory functions of glial with a particular focus on their involvement inflammation cascades initiated by accumulation alpha-synuclein (α-syn), hallmark Parkinson’s disease (PD). Deriving insights from studies both sporadic familial forms PD, as well animal models we explore how cells contribute progression triggered α-syn aggregation. Additionally, analyze interplay between blood-brain barrier (BBB), highlighting role these BBB integrity permeability context PD pathology. Furthermore, delve into potential activation repair neuroprotective mechanisms mediated amidst α-syn-induced neuroinflammation. By integrating information dynamics, this aims deepen our understanding multifaceted interactions pathology, CNS inflammation, thereby offering valuable therapeutic strategies for related neurodegenerative disorders.

Language: Английский

Citations

2
Alpha-synuclein inclusion responsive microglia are resistant to CSF1R inhibition DOI Creative Commons
Anna C. Stoll,

Christopher J. Kemp,

Joseph R. Patterson

et al.

Journal of Neuroinflammation, Journal Year: 2024, Volume and Issue: 21(1)

Published: April 25, 2024

Abstract Background Parkinson’s disease (PD) is a neurodegenerative disorder that characterized by the presence of proteinaceous alpha-synuclein (α-syn) inclusions (Lewy bodies), markers neuroinflammation and progressive loss nigrostriatal dopamine (DA) neurons. These pathological features can be recapitulated in vivo using α-syn preformed fibril (PFF) model synucleinopathy. We have previously determined microglia proximal to PFF-induced nigral increase soma size, upregulate major-histocompatibility complex-II (MHC-II) expression, expression suite inflammation-associated transcripts. This microglial response observed months prior degeneration, suggesting reacting inclusion may contribute neurodegeneration could represent potential target for novel therapeutics. The goal this study was determine whether colony stimulating factor-1 receptor (CSF1R)-mediated depletion impacts magnitude aggregation, or context PFF model. Methods Male Fischer 344 rats were injected intrastriatally with either PFFs saline. Rats continuously administered Pexidartinib (PLX3397B, 600 mg/kg), CSF1R inhibitor, deplete period 2 6 months. Results inhibition resulted significant (~ 43%) ionized calcium-binding adapter molecule 1 immunoreactive (Iba-1ir) within SNpc. However, did not impact number, number MHC-II Cd74 , Cxcl10 Rt-1a2 Grn Csf1r Tyrobp Fcer1g associated phosphorylated (pSyn) inclusions. Further, accumulation pSyn degeneration neurons impacted inhibition. Paradoxically, long term increased size remaining Iba-1ir both control rats, as well extranigral regions. Conclusions Collectively, our results suggest does viable disease-modifying strategy PD.

Language: Английский

Citations

1