Dataset Information

Neurexophilin4 is a selectively expressed ?-neurexin ligand that modulates specific cerebellar synapses and motor functions.

ABSTRACT: Neurexophilins are secreted neuropeptide-like glycoproteins, and neurexophilin1 and neurexophilin3 are ligands for the presynaptic cell adhesion molecule ?-neurexin. Neurexophilins are more selectively expressed in the brain than ?-neurexins, however, which led us to ask whether neurexophilins modulate the function of ?-neurexin in a context-specific manner. We characterized the expression and function of neurexophilin4 in mice and found it to be expressed in subsets of neurons responsible for feeding, emotion, balance, and movement. Deletion of Neurexophilin4 caused corresponding impairments, most notably in motor learning and coordination. We demonstrated that neurexophilin4 interacts with ?-neurexin and GABA_ARs in the cerebellum. Loss of Neurexophilin4 impaired cerebellar Golgi-granule inhibitory neurotransmission and synapse number, providing a partial explanation for the motor learning and coordination deficits observed in the Neurexophilin4 null mice. Our data illustrate how selectively expressed Neurexophilin4, an ?-neurexin ligand, regulates specific synapse function and modulates cerebellar motor control.

SUBMITTER: Meng X

PROVIDER: S-EPMC6763262 | biostudies-literature | 2019 Sep

REPOSITORIES: biostudies-literature

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Neurexophilin4 is a selectively expressed α-neurexin ligand that modulates specific cerebellar synapses and motor functions.

Meng Xiangling X McGraw Christopher M CM Wang Wei W Jing Junzhan J Yeh Szu-Ying SY Wang Li L Lopez Joanna J Brown Amanda M AM Lin Tao T Chen Wu W Xue Mingshan M Sillitoe Roy V RV Jiang Xiaolong X Zoghbi Huda Y HY

eLife 20190916

Neurexophilins are secreted neuropeptide-like glycoproteins, and neurexophilin1 and neurexophilin3 are ligands for the presynaptic cell adhesion molecule α-neurexin. Neurexophilins are more selectively expressed in the brain than α-neurexins, however, which led us to ask whether neurexophilins modulate the function of α-neurexin in a context-specific manner. We characterized the expression and function of neurexophilin4 in mice and found it to be expressed in subsets of neurons responsible for f ...[more]

PMID: 31524598

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Project description:Neurexins are a large family of neuronal plasma membrane proteins, which function as trans-synaptic receptors during synaptic differentiation. The binding of presynaptic neurexins to postsynaptic partners, such as neuroligins, has been proposed to participate in a signaling pathway that regulates synapse formation/stabilization. The identification of mutations in neurexin genes associated with autism and mental retardation suggests that dysfunction of neurexins may underlie synaptic defects associated with brain disorders. However, the mechanisms that regulate neurexin function at synapses are still unclear. Here, we show that neurexins are proteolytically processed by presenilins (PS), the catalytic components of the γ-secretase complex that mediates the intramembraneous cleavage of several type I membrane proteins. Inhibition of PS/γ-secretase by using pharmacological and genetic approaches induces a drastic accumulation of neurexin C-terminal fragments (CTFs) in cultured rat hippocampal neurons and mouse brain. Neurexin-CTFs accumulate mainly at the presynaptic terminals of PS conditional double knockout (PS cDKO) mice lacking both PS genes in glutamatergic neurons of the forebrain. The fact that loss of PS function enhances neurexin accumulation at glutamatergic terminals mediated by neuroligin-1 suggests that PS regulate the processing of neurexins at glutamatergic synapses. Interestingly, presenilin 1 (PS1) is recruited to glutamatergic terminals mediated by neuroligin-1, thus concentrating PS1 at terminals containing β-neurexins. Furthermore, familial Alzheimer's disease (FAD)-linked PS1 mutations differentially affect β-neurexin-1 processing. Expression of PS1 M146L and PS1 H163R mutants in PS-/- cells rescues the processing of β-neurexin-1, whereas PS1 C410Y and PS1 ΔE9 fail to rescue the processing defect. These results suggest that PS regulate the synaptic function and processing of neurexins at glutamatergic synapses, and that impaired neurexin processing by PS may play a role in FAD.

Project description:Background: Parkinson's disease (PD) results in both motor and non-motor symptoms. Traditionally, the underlying mechanism of PD has been linked to neurodegeneration of the basal ganglia. Yet it does not adequately account for the non-motor symptoms of the disease, suggesting that other brain regions may be involved. One such region is the cerebellum, which is known to be involved, together with the basal ganglia, in both motor and non-motor functions. Many studies have found the cerebellum to be hyperactive in PD patients, a finding that is seldom discussed in detail, and warrants further examination. The current study thus aims to examine quantitively the current literature on the cerebellar involvement in both motor and non-motor functioning in PD. Methods: A meta-analysis of functional neuroimaging literature was conducted with Seed-based D mapping. Only the studies testing functional activation in response to motor and non-motor paradigms in PD and healthy controls (HC) were included in the meta-analysis. Separate analyses were conducted by including only studies with non-motor paradigms, as well as meta-regressions with UPDRS III scores and disease duration. Results: A total of 57 studies with both motor and non-motor paradigms fulfilled our inclusion criteria and were included in the meta-analysis, which revealed hyperactivity in Crus I-II and vermal III in PD patients compared to HC. An analysis including only studies with cognitive paradigms revealed a cluster of increased activity in PD patients encompassing lobule VIIB and VIII. Another meta-analysis including the only 20 studies that employed motor paradigms did not reveal any significant group differences. However, a descriptive analysis of these studies revealed that 60% of them reported cerebellar hyperactivations in PD and included motor paradigm with significant cognitive task demands, as opposed to 40% presenting the opposite pattern and using mainly force grip tasks. The meta-regression with UPDRS III scores found a negative association between motor scores and activation in lobule VI and vermal VII-VIII. No correlation was found with disease duration. Discussion: The present findings suggest that one of the main cerebellar implications in PD is linked to cognitive functioning. The negative association between UPDRS scores and activation in regions implicated in motor functioning indicate that there is less involvement of these areas as the disease severity increases. In contrast, the lack of correlation with disease duration seems to indicate that the cerebellar activity may be a compensatory mechanism to the dysfunctional basal ganglia, where certain sub-regions of the cerebellum are employed to cope with motor demands. Yet future longitudinal studies are needed to fully address this possibility.

Dataset Information

Neurexophilin4 is a selectively expressed ?-neurexin ligand that modulates specific cerebellar synapses and motor functions.

Publications

Neurexophilin4 is a selectively expressed α-neurexin ligand that modulates specific cerebellar synapses and motor functions.

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