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Netrin‐1 is a chemotropic cue mediating axon growth and neural migration in neuronal development, and its receptors deletion in colorectal cancer and UNC5s act as dependence receptors regulating neuronal apoptosis. Asparagine endopeptidase (AEP) is an age‐dependent protease that cuts human alpha‐synuclein (α‐Syn) at N103 and triggers its aggregation and neurotoxicity. In the current study, it is reported that UNC5C receptor is cleaved by AEP in Parkinson's disease (PD) and facilitates dopaminergic neuronal loss. UNC5C is truncated by active AEP in human α‐SNCA transgenic mice in an age‐dependent manner or induced by neurotoxin rotenone. Moreover, UNC5C is fragmented by AEP in PD brains, inversely correlated with reduced netrin‐1 levels. Netrin‐1 deprivation in primary cultures induces AEP and caspase‐3 activation, triggering UNC5C proteolytic fragmentation and enhancing neuronal loss. Noticeably, blocking UNC5C cleavage by AEP attenuates netrin‐1 deprivation‐elicited neuronal death and motor disorders in netrin flox/flox mice. Overexpression of AEP‐truncated UNC5C intracellular fragment strongly elicits α‐Syn aggregation and dopaminergic loss, locomotor deficits in α‐SNCA transgenic mice. Hence, the findings demonstrate that netrin‐1 reduction and UNC5C truncation by AEP contribute to PD pathogenesis. [ABSTRACT FROM AUTHOR]

Aims: Alterations in neuronal activity and cerebral hemodynamics have been reported in idiopathic generalized epilepsy (IGE) patients, possibly resulting in neurovascular decoupling; however, no neuroimaging evidence confirmed this disruption. This study aimed to investigate the possible presence of neurovascular decoupling and its clinical implications in childhood IGE using resting‐state fMRI and arterial spin labeling imaging. Methods: IGE patients and healthy participants underwent resting‐state fMRI and arterial spin labeling imaging to calculate degree centrality (DC) and cerebral blood flow (CBF), respectively. Across‐voxel CBF‐DC correlations were analyzed to evaluate the neurovascular coupling within the whole gray matter, and the regional coupling of brain region was assessed with the CBF/DC ratio. Results: The study included 26 children with IGE and 35 sex‐ and age‐matched healthy controls (HCs). Compared with the HCs, the IGE group presented lower across‐voxel CBF‐DC correlations, higher CBF/DC ratio in the right posterior cingulate cortex/precuneus, middle frontal gyrus, and medial frontal gyrus (MFG), and lower ratio in the left inferior frontal gyrus. The increased CBF/DC ratio in the right MFG was correlated with lower performance intelligence quotient scores in the IGE group. Conclusion: Children with IGE present altered neurovascular coupling, associated with lower performance intelligence quotient scores. The study shed a new insight into the pathophysiology of epilepsy and provided potential imaging biomarkers of cognitive performances in children with IGE. [ABSTRACT FROM AUTHOR]

DJ‐1, also known as Parkinson's disease protein 7 (Park7), is a multifunctional protein that regulates oxidative stress and mitochondrial function. Dysfunction of DJ‐1 is implicated in the pathogenesis of Parkinson's disease (PD). Hyperhomocysteinemia is associated with an increased risk of PD. Here we show that homocysteine thiolactone (HTL), a reactive thioester of homocysteine (Hcy), covalently modifies DJ‐1 on the lysine 182 (K182) residue in an age‐dependent manner. The N‐homocysteinylation (N‐hcy) of DJ‐1 abolishes its neuroprotective effect against oxidative stress and mitochondrial dysfunction, exacerbating cell toxicity. Blocking the N‐hcy of DJ‐1 restores its protective effect. These results indicate that the N‐hcy of DJ‐1 abolishes its neuroprotective effect and promotes the progression of PD. Inhibiting the N‐hcy of DJ‐1 may exert neuroprotective effect against PD. [ABSTRACT FROM AUTHOR]

Cerebral oedema is a major pathological change of acute carbon monoxide (CO) poisoning, the pathogenesis of which is still unclear. In the aquaporin (AQP) water channel family, AQP1 and AQP4 play critical roles in the progress of cerebral oedema of various neuropathological events. However, their functions in CO poisoning have not been demonstrated. In this study, we investigated the expressions of AQPs and associated mechanisms of brain injury in an acute CO poisoning rat model. Compared with the control injected intraperitoneally with equal volume of air, the dry weight/wet weight (DW/WW) ratio of brain water content, levels of AQP1, AQP4, phosph‐p38 mitogen‐activated protein kinase (p‐p38 MAPK) and astrocyte marker, glial fibrillary acidic protein (GFAP) in the frontal cortex and hippocampal CA1 of acute CO poisoning group significantly increased at 6, 12, 24 hours after CO injection. Intracerebroventricular injection with a p38 MAPK inhibitor, SB203580 (200 µmol/L/kg/d), before CO injection reduced water content in the brain tissues and significantly decreased levels of AQP1, AQP4, p‐p38 MAPK and GFAP. Therefore, our study showed that the overexpressions of AQP1 and AQP4 were involved in the development of CO poisoning‐induced cerebral oedema, which could be attenuated by inhibition of p‐p38 MAPK signalling. Manipulation of AQPs and p38 MAPK may be a new therapeutic strategy for acute CO poisoning. [ABSTRACT FROM AUTHOR]

The aggregation of α‐synuclein plays a pivotal role in the pathogenesis of Parkinson's disease (PD). Epidemiological evidence indicates that high level of homocysteine (Hcy) is associated with an increased risk of PD. However, the molecular mechanisms remain elusive. Here, we report that homocysteine thiolactone (HTL), a reactive thioester of Hcy, covalently modifies α‐synuclein on the K80 residue. The levels of α‐synuclein K80Hcy in the brain are increased in an age‐dependent manner in the TgA53T mice, correlating with elevated levels of Hcy and HTL in the brain during aging. The N‐homocysteinylation of α‐synuclein stimulates its aggregation and forms fibrils with enhanced seeding activity and neurotoxicity. Intrastriatal injection of homocysteinylated α‐synuclein fibrils induces more severe α‐synuclein pathology and motor deficits when compared with unmodified α‐synuclein fibrils. Increasing the levels of Hcy aggravates α‐synuclein neuropathology in a mouse model of PD. In contrast, blocking the N‐homocysteinylation of α‐synuclein ameliorates α‐synuclein pathology and degeneration of dopaminergic neurons. These findings suggest that the covalent modification of α‐synuclein by HTL promotes its aggregation. Targeting the N‐homocysteinylation of α‐synuclein could be a novel therapeutic strategy against PD. [ABSTRACT FROM AUTHOR]

Synaptic dysfunction is a key feature of Alzheimer's disease (AD). However, the molecular mechanisms underlying synaptic dysfunction remain unclear. Here, we show that synapsin Ⅰ, one of the most important synaptic proteins, is fragmented by the cysteine proteinase asparagine endopeptidase (AEP). AEP cleaves synapsin at N82 in the brains of AD patients and generates the C‐terminal synapsin Ⅰ (83–705) fragment. This fragment is abnormally distributed in neurons and induces synaptic dysfunction. Overexpression of AEP in the hippocampus of wild‐type mice results in the production of the synapsin Ⅰ (83–705) fragment and induces synaptic dysfunction and cognitive deficits. Moreover, overexpression of the AEP‐generated synapsin Ⅰ (83–705) fragment in the hippocampus of tau P301S transgenic mice and wild‐type mice promotes synaptic dysfunction and cognitive deficits. These findings suggest a novel mechanism of synaptic dysfunction in AD. [ABSTRACT FROM AUTHOR]