Conserved and cell type-specific transcriptional responses to IFN-γ in the ventral midbrain

Hobson, Benjamin D.; Stanley, Adrien; Santos, Mark B. De Los; Culbertson, Bruce; Mosharov, Eugene V.; Sims, Peter A.; Sulzer, David

doi:10.1016/j.bbi.2023.04.008

Cited by 2 publications

(3 citation statements)

References 99 publications

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“…IFNγ induces neuroinflammation and DA neurodegeneration primarily through IFNγ receptor (IFNGR)-dependent canonical signaling 47 . In fact, animals lacking IFNGR are reportedly completely unresponsive to IFNγ stimulation, indicating the crucial role of IFNGR in mediating its effects 33 . In this study, we found that IFNγ upregulated the protein level of LRRK2 and increased the expression of IFNGR-2 in astrocytes markedly while mutant LRRK2 mice treated with IFNγ.…”

Section: Discussionmentioning

confidence: 99%

“…Interestingly, glymphatic impairment can be reversed by inhibiting LRRK2, suggesting that targeting LRRK2 activity might break the vicious cycle. Notably, IFNγ might also induce neuroinflammation and neurotoxicity in other cell types 33 . In the present study, we were unable to detect IFNGR-2 expression in microglia, suggesting that IFNγ alone is insufficient to induce microglial IFNGR-2 expression.…”

Section: Discussionmentioning

confidence: 99%

“…Other studies have reported that IFNγ requires additional inflammatory stimulators, such as LPS, to activate microglia 49 . However, IFNγ reportedly increases the expression of major histocompatibility complex (MHC)-I in neurons and MHC-I/II in microglia 33 . Further investigations are needed to explore the specific contributions of different cell types in LRRK2 -associated PD.…”

Section: Discussionmentioning

confidence: 99%

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Phosphorylation of AQP4 by LRRK2 R1441G impairs glymphatic clearance of IFNγ and aggravates dopaminergic neurodegeneration

Huang,

Lin,

et al. 2024

npj Parkinsons Dis.

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Aquaporin-4 (AQP4) is essential for normal functioning of the brain’s glymphatic system. Impaired glymphatic function is associated with neuroinflammation. Recent clinical evidence suggests the involvement of glymphatic dysfunction in LRRK2-associated Parkinson’s disease (PD); however, the precise mechanism remains unclear. The pro-inflammatory cytokine interferon (IFN) γ interacts with LRRK2 to induce neuroinflammation. Therefore, we examined the AQP4-dependent glymphatic system’s role in IFNγ-mediated neuroinflammation in LRRK2-associated PD. We found that LRRK2 interacts with and phosphorylates AQP4 in vitro and in vivo. AQP4 phosphorylation by LRRK2 R1441G induced AQP4 depolarization and disrupted glymphatic IFNγ clearance. Exogeneous IFNγ significantly increased astrocyte expression of IFNγ receptor, amplified AQP4 depolarization, and exacerbated neuroinflammation in R1441G transgenic mice. Conversely, inhibiting LRRK2 restored AQP4 polarity, improved glymphatic function, and reduced IFNγ-mediated neuroinflammation and dopaminergic neurodegeneration. Our findings establish a link between LRRK2-mediated AQP4 phosphorylation and IFNγ-mediated neuroinflammation in LRRK2-associated PD, guiding the development of LRRK2 targeting therapy.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Phosphorylation of AQP4 by LRRK2 R1441G impairs glymphatic clearance of IFNγ and aggravates dopaminergic neurodegeneration

Huang,

Lin,

et al. 2024

npj Parkinsons Dis.

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Differentiation and regulation of CD4+ T cell subsets in Parkinson’s disease

Sun,

Gu,

Bai

2024

Cell. Mol. Life Sci.

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Parkinson’s disease (PD) is the second most common neurodegenerative disease, and its hallmark pathological features are the loss of dopaminergic (DA) neurons in the midbrain substantia nigra pars compacta (SNpc) and the accumulation of alpha-synuclein (α-syn). It has been shown that the integrity of the blood-brain barrier (BBB) is damaged in PD patients, and a large number of infiltrating T cells and inflammatory cytokines have been detected in the cerebrospinal fluid (CSF) and brain parenchyma of PD patients and PD animal models, including significant change in the number and proportion of different CD4 + T cell subsets. This suggests that the neuroinflammatory response caused by CD4 + T cells is an important risk factor for the development of PD. Here, we systematically review the differentiation of CD4 + T cell subsets, and focus on describing the functions and mechanisms of different CD4 + T cell subsets and their secreted cytokines in PD. We also summarize the current immunotherapy targeting CD4 + T cells with a view to providing assistance in the diagnosis and treatment of PD.

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Conserved and cell type-specific transcriptional responses to IFN-γ in the ventral midbrain

Cited by 2 publications

References 99 publications

Phosphorylation of AQP4 by LRRK2 R1441G impairs glymphatic clearance of IFNγ and aggravates dopaminergic neurodegeneration

Phosphorylation of AQP4 by LRRK2 R1441G impairs glymphatic clearance of IFNγ and aggravates dopaminergic neurodegeneration

Differentiation and regulation of CD4+ T cell subsets in Parkinson’s disease

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