Mesencephalic astrocyte-derived neurotrophic factor (MANF) prevents the neuroinflammation induced dopaminergic neurodegeneration

Zhang, Jingxing; Zhou, Kai-Ge; Yin, Yanxin; Jin, Lingjing; Tong, Weifang; Guo, Jia; Yu, Lihua; Ye, Xian-Cheng; Jiang, Ming

doi:10.1016/j.exger.2022.112037

Cited by 14 publications

(9 citation statements)

References 30 publications

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“…Astrocytes are generally recognized to play supporting roles in the brain, yet emerging researches have pointed out more direct roles of astrocytes for brain functions (Fee et al, 2017 ; Rajkowska & Stockmeier, 2013 ; Tripp et al, 2011 ). For example, much evidence from rodent models indicated that astrocytes could not only detect serotonin and noradrenaline in synaptic transmission, but also uptaked these neurotransmitters (Guo et al, 2022 ; Portal et al, 2022 ; Zhang et al, 2023 ). The mechanism of astrocytes involvement in MDD was thought to be through influencing synaptic activity and modulating neuronal circuits, such as an imbalance between excitatory and inhibitory neurons (Anderson, Collins, Chin, et al, 2020 ; Li, Seidlitz, et al, 2021 ).…”

Section: Discussionmentioning

confidence: 99%

Compressed primary‐to‐transmodal gradient is accompanied with subcortical alterations and linked to neurotransmitters and cellular signatures in major depressive disorder

Xiao,

Zhao,

Zang

et al. 2023

Human Brain Mapping

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Major depressive disorder (MDD) has been shown to involve widespread changes in low‐level sensorimotor and higher‐level cognitive functions. Recent research found that a primary‐to‐transmodal gradient could capture a cortical hierarchical organization ranging from perception and action to cognition in healthy subjects, but a prominent gradient dysfunction in MDD patients. However, whether and how this cortical gradient is linked to subcortical impairments and whether it is reflected in the microscale neurotransmitter systems and cell type‐specific transcriptional signatures remain largely unknown. Data were acquired from 323 MDD patients and 328 sex‐ and age‐matched healthy controls derived from the REST‐meta‐MDD project, and the human brain neurotransmitter systems density maps and gene expression data were drawn from two publicly available datasets. We investigated alterations of the primary‐to‐transmodal gradient in MDD patients and their correlations with clinical symptoms of depression and anxiety, as well as their paralleled subcortical impairments. The correlations between MDD‐related gradient alterations and densities of the neurotransmitter systems and gene expression information were assessed, respectively. The results demonstrated that MDD patients had a compressed primary‐to‐transmodal gradient accompanied by paralleled alterations in subcortical regions including the caudate, amygdala, and thalamus. The case–control gradient differences were spatially correlated with the densities of the neurotransmitter systems including the serotonin and dopamine receptors, and meanwhile with gene expression enriched in astrocytes, excitatory and inhibitory neuronal cells. These findings mapped the paralleled subcortical impairments in cortical hierarchical organization and also helped us understand the possible molecular and cellular substrates of the co‐occurrence of high‐level cognitive impairments with low‐level sensorimotor abnormalities in MDD.

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Section: Discussionmentioning

confidence: 99%

Compressed primary‐to‐transmodal gradient is accompanied with subcortical alterations and linked to neurotransmitters and cellular signatures in major depressive disorder

Xiao,

Zhao,

Zang

et al. 2023

Human Brain Mapping

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“…Inspection of intrastriatally injected iodinated MANF showed transport to the cortex but not to the SN, indicating effective retrograde and inefficient anterograde transport (14). While lentivirus vector-mediated MANF overexpression in the striatum did not promote dopamine neuron function or survival in 6-OHDA model (109), intrastriatal AAV9-mediated gene delivery of MANF, in turn, showed a significant improvement in 6-OHDAtreated rats (120). Hao and others (120) reported an increase in the survival of midbrain dopamine neurons and an increase in striatal dopamine levels in addition to reduced amphetamine-induced rotations.…”

Section: Cdnf Manf and In Vivo Pd Modelsmentioning

confidence: 99%

“…While lentivirus vector-mediated MANF overexpression in the striatum did not promote dopamine neuron function or survival in 6-OHDA model (109), intrastriatal AAV9-mediated gene delivery of MANF, in turn, showed a significant improvement in 6-OHDAtreated rats (120). Hao and others (120) reported an increase in the survival of midbrain dopamine neurons and an increase in striatal dopamine levels in addition to reduced amphetamine-induced rotations. Similarly, AAV8-vector-mediated MANF expression in the striatum resulted in improved motor behavior and survival of TH-positive neurons in the SN in a 6-OHDA rat model of PD (121).…”

Section: Cdnf Manf and In Vivo Pd Modelsmentioning

confidence: 99%

CDNF and MANF in the brain dopamine system and their potential as treatment for Parkinson’s disease

Pakarinen

Lindholm

2023

Front. Psychiatry

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Parkinson’s disease (PD) is a progressive neurodegenerative disease characterized by gradual loss of midbrain dopamine neurons, leading to impaired motor function. Preclinical studies have indicated cerebral dopamine neurotrophic factor (CDNF) and mesencephalic astrocyte-derived neurotrophic factor (MANF) to be potential therapeutic molecules for the treatment of PD. CDNF was proven to be safe and well tolerated when tested in Phase I-II clinical trials in PD patients. Neuroprotective and neurorestorative effects of CDNF and MANF were demonstrated in animal models of PD, where they promoted the survival of dopamine neurons and improved motor function. However, biological roles of endogenous CDNF and MANF proteins in the midbrain dopamine system have been less clear. In addition to extracellular trophic activities, CDNF/MANF proteins function intracellularly in the endoplasmic reticulum (ER), where they modulate protein homeostasis and protect cells against ER stress by regulating the unfolded protein response (UPR). Here, our aim is to give an overview of the biology of endogenous CDNF and MANF in the brain dopamine system. We will discuss recent studies on CDNF and MANF knockout animal models, and effects of CDNF and MANF in preclinical models of PD. To elucidate possible roles of CDNF and MANF in human biology, we will review CDNF and MANF tissue expression patterns and regulation of CDNF/MANF levels in human diseases. Finally, we will discuss novel findings related to the molecular mechanism of CDNF and MANF action in ER stress, UPR, and inflammation, all of which are mechanisms potentially involved in the pathophysiology of PD.

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“…Neurotrophins (GDNF, MANF, CDNF) hold the potential of restoring degenerated neurons, but these proteins would require delivery by specific vectors or use of small-molecule mimetics. Moreover, CDNF was presented to reduce α-syn aggregation [ 379 ] and both MANF and CDNF to alleviate ER stress, neuroinflammation and apoptosis [ 380 , 381 ].…”

Section: Drugs Targeting α-Synucleinmentioning

confidence: 99%

Inhibition of Protein Aggregation and Endoplasmic Reticulum Stress as a Targeted Therapy for α-Synucleinopathy

Siwecka,

Saramowicz,

Galita

et al. 2023

Pharmaceutics

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α-synuclein (α-syn) is an intrinsically disordered protein abundant in the central nervous system. Physiologically, the protein regulates vesicle trafficking and neurotransmitter release in the presynaptic terminals. Pathologies related to misfolding and aggregation of α-syn are referred to as α-synucleinopathies, and they constitute a frequent cause of neurodegeneration. The most common α-synucleinopathy, Parkinson’s disease (PD), is caused by abnormal accumulation of α-syn in the dopaminergic neurons of the midbrain. This results in protein overload, activation of endoplasmic reticulum (ER) stress, and, ultimately, neural cell apoptosis and neurodegeneration. To date, the available treatment options for PD are only symptomatic and rely on dopamine replacement therapy or palliative surgery. As the prevalence of PD has skyrocketed in recent years, there is a pending issue for development of new disease-modifying strategies. These include anti-aggregative agents that target α-syn directly (gene therapy, small molecules and immunization), indirectly (modulators of ER stress, oxidative stress and clearance pathways) or combine both actions (natural compounds). Herein, we provide an overview on the characteristic features of the structure and pathogenic mechanisms of α-syn that could be targeted with novel molecular-based therapies.

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Mesencephalic astrocyte-derived neurotrophic factor (MANF) prevents the neuroinflammation induced dopaminergic neurodegeneration

Cited by 14 publications

References 30 publications

Compressed primary‐to‐transmodal gradient is accompanied with subcortical alterations and linked to neurotransmitters and cellular signatures in major depressive disorder

Compressed primary‐to‐transmodal gradient is accompanied with subcortical alterations and linked to neurotransmitters and cellular signatures in major depressive disorder

CDNF and MANF in the brain dopamine system and their potential as treatment for Parkinson’s disease

Inhibition of Protein Aggregation and Endoplasmic Reticulum Stress as a Targeted Therapy for α-Synucleinopathy

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