VAP-SCRN1 interaction regulates dynamic endoplasmic reticulum remodeling and presynaptic function.

In neurons, the continuous and dynamic endoplasmic reticulum (ER) network extends throughout the axon, and its dysfunction causes various axonopathies. However, it remains largely unknown how ER integrity and remodeling modulate presynaptic function in mammalian neurons. Here, we demonstrated that ER membrane receptors VAPA and VAPB are involved in modulating the synaptic vesicle (SV) cycle. VAP interacts with secernin-1 (SCRN1) at the ER membrane via a single FFAT-like motif. Similar to VAP, loss of SCRN1 or SCRN1-VAP interactions resulted in impaired SV cycling. Consistently, SCRN1 or VAP depletion was accompanied by decreased action potential-evoked Ca2+ responses. Additionally, we found that VAP-SCRN1 interactions play an important role in maintaining ER continuity and dynamics, as well as presynaptic Ca2+ homeostasis. Based on these findings, we propose a model where the ER-localized VAP-SCRN1 interactions provide a novel control mechanism to tune ER remodeling and thereby modulate Ca2+ dynamics and SV cycling at presynaptic sites. These data provide new insights into the molecular mechanisms controlling ER structure and dynamics, and highlight the relevance of ER function for SV cycling.

SCRN1: A cerebrospinal fluid biomarker correlating with tau in Alzheimer's disease.

INTRODUCTION: Secernin-1 (SCRN1) is a neuronal protein that co-localizes with neurofibrillary tangles in Alzheimer's disease (AD), but not with tau inclusions in corticobasal degeneration (CBD), progressive supranuclear palsy (PSP), or Pick's disease. METHODS: We measured SCRN1 concentration in cerebrospinal fluid (CSF) using a novel mass spectrometric parallel reaction monitoring method in three clinical cohorts comprising patients with neurochemically characterized AD (n = 25) and controls (n = 28), clinically diagnosed Parkinson's disease (PD; n = 38), multiple system atrophy (MSA; n = 31), PSP (n = 20), CBD (n = 8), healthy controls (n = 37), and neuropathology-confirmed AD (n = 47). RESULTS: CSF SCRN1 was significantly increased in AD (P < 0.01, fold change = 1.4) compared to controls (receiver operating characteristic area under the curve = 0.78) but not in CBD, PSP, PD, or MSA. CSF SCRN1 positively correlated with CSF total tau (R = 0.78, P = 1.1 × 10-13 ), phosphorylated tau181 (R = 0.64, P = 3.2 × 10-8 ), and Braak stage and negatively correlated with Mini-Mental State Examination score. DISCUSSION: CSF SCRN1 is a candidate biomarker of AD, reflecting tau pathology. HIGHLIGHTS: We developed a parallel reaction monitoring assay to measure secernin-1 (SCRN1) in cerebrospinal fluid (CSF). CSF SCRN1 was increased in Alzheimer's disease compared to healthy controls. CSF SCRN1 remained unchanged in Parkinson's disease, multiple system atrophy, progressive supranuclear palsy, or corticobasal degeneration compared to controls. CSF SCRN1 correlated strongly with CSF phosphorylated tau and total tau. CSF SCRN1 increased across Braak stages and negatively correlated with Mini-Mental State Examination score.

Diosgenin upregulates axonal guidance partner molecules, Galectin-1 and Secernin-1.

Galectin-1, a ß-galactosides-binding protein, is widely expressed in various tissues and exhibits diverse biological activities. We previously obtained following findings; 1) Diosgenin, a steroid sapogenin, promoted axonal regeneration in the brain and recovered memory deficits in a model of Alzheimer's disease (AD), 5XFAD mouse; 2) Neuron-specific overexpression of Galectin-1 protein in the hippocampus recovered memory impairment and promoted axonal regeneration in the brain in 5XFAD mice; 3) Secernin-1, a counterpart and axonal guidance molecule for Galectin-1-expressing axons, was secreted from the prefrontal cortical neurons to promote axonal guidance from the hippocampus to the prefrontal cortex. However, it has never been elucidated that diosgenin signaling increase Galectin-1 and Secernin-1 or not. Here, we found that diosgenin treatment upregulated the protein level of Galectin-1 in the hippocampus both in primary cultured neurons and in 5XFAD mouse brains. In addition, diosgenin-induced upregulation of Galectin-1 was diminished by treatment of a neutralizing antibody of 1,25D3-membrane-associated rapid response steroid-binding receptor (1,25D3-MARRS), a direct binding receptor for diosgenin. Importantly, knockdown of Galectin-1 in hippocampal neurons inhibited axonal growth activity of diosgenin. Furthermore, the expression level of Secernin-1 was also increased in prefrontal cortical neurons by administration of diosgenin to 5XFAD mice. These findings suggest that diosgenin is a suitable compound to facilitate Galectin-1-Secernin-1-mediated axonal growth in AD brains.

Axonal Regeneration Mediated by a Novel Axonal Guidance Pair, Galectin-1 and Secernin-1.

Galectin-1 (Gal-1), a member of the Galectin family, is expressed in various tissues and responsible for multiple biological activities. Previous studies reported that extracellular Gal-1 participated in axonal growth and repair, and Gal-1 knockout mice exhibited memory impairment. However, no study has demonstrated the direct contribution of intracellular Gal-1 upregulation in neurons to promoting axonal regeneration in the brain and recovering memory function. In the present study, we found that axonal growth is promoted by overexpression of Gal-1 via adeno-associated virus serotype 9 delivery in primary cultured hippocampal neurons. Moreover, Gal-1 was expressed on the membranes of growth cones in hippocampal neurons and interacted with a novel axonal guidance molecule, Secernin-1, which was secreted from prefrontal cortex (PFC) neurons. Gal-1-overexpression-driven axonal growth was enhanced when recombinant (extracellular) Secernin-1 was treated to the axonal site in a neuron device chamber. Direct binding of extracellular Secernin-1 with Gal-1 was detected through immunoprecipitation and immunocytochemistry, demonstrating that Gal-1 possibly works as an axonal guidance receptor for Secernin-1 in hippocampal neurons. In the PFC, the expression of Gal-1 in axonal shafts and terminals of hippocampal neurons was decreased in the 5XFAD mouse model of Alzheimer's disease (AD). Overexpression of Gal-1 in hippocampal neurons recovered memory deficits and induced axonal regeneration toward the PFC in 5XFAD mice. This study suggests that the enhanced interaction of Secernin-1 and Gal-1 can be harnessed as a therapeutic strategy for long-distance and direction-specific axonal regeneration in AD.

Secernin-1 is a novel phosphorylated tau binding protein that accumulates in Alzheimer's disease and not in other tauopathies.

We recently identified Secernin-1 (SCRN1) as a novel amyloid plaque associated protein using localized proteomics. Immunohistochemistry studies confirmed that SCRN1 was present in plaque-associated dystrophic neurites and also revealed distinct and abundant co-localization with neurofibrillary tangles (NFTs). Little is known about the physiological function of SCRN1 and its role in Alzheimer's disease (AD) and other neurodegenerative diseases has not been studied. Therefore, we performed a comprehensive study of SCRN1 distribution in neurodegenerative diseases. Immunohistochemistry was used to map SCRN1 accumulation throughout the progression of AD in a cohort of 58 patients with a range of NFT pathology (Abundant NFT, n = 21; Moderate NFT, n = 22; Low/No NFT, n = 15), who were clinically diagnosed as having AD, mild cognitive impairment or normal cognition. SCRN1 accumulation was also examined in two cases with both Frontotemporal Lobar Degeneration (FTLD)-Tau and AD-related neuropathology, cases of Down Syndrome (DS) with AD (n = 5), one case of hereditary cerebral hemorrhage with amyloidosis - Dutch type (HCHWA-D) and other non-AD tauopathies including: primary age-related tauopathy (PART, [n = 5]), Corticobasal Degeneration (CBD, [n = 5]), Progressive Supranuclear Palsy (PSP, [n = 5]) and Pick's disease (PiD, [n = 4]). Immunohistochemistry showed that SCRN1 was a neuronal protein that abundantly accumulated in NFTs and plaque-associated dystrophic neurites throughout the progression of AD. Quantification of SCRN1 immunohistochemistry confirmed that SCRN1 preferentially accumulated in NFTs in comparison to surrounding non-tangle containing neurons at both early and late stages of AD. Similar results were observed in DS with AD and PART. However, SCRN1 did not co-localize with phosphorylated tau inclusions in CBD, PSP or PiD. Co-immunoprecipitation revealed that SCRN1 interacted with phosphorylated tau in human AD brain tissue. Together, these results suggest that SCRN1 is uniquely associated with tau pathology in AD, DS and PART. As such, SCRN1 has potential as a novel therapeutic target and could serve as a useful biomarker to distinguish AD from other tauopathies.

Metastatic biomarkers in synovial sarcoma.

Synovial sarcoma (SS) is an aggressive soft tissue sarcoma (STS) that typically occurs in the extremities near a joint. Metastatic disease is common and usually occurs in the lungs and lymph nodes. Surgical management is the mainstay of treatment with chemotherapy and radiation typically used as adjuvant treatment. Although chemotherapy has a positive impact on survival, the prognosis is poor if metastatic disease occurs. The biology of sarcoma invasion and metastasis remain poorly understood. Chromosomal translocation with fusion of the SYT and SSX genes has been described and is currently used as a diagnostic marker, although the full impact of the fusion is unknown. Multiple biomarkers have been found to be associated with SS and are currently under investigation regarding their pathways and mechanisms of action. Further research is needed in order to develop better diagnostic screening tools and understanding of tumor behavior. Development of targeted therapies that reduce metastatic events in SS, would dramatically improve patient prognosis.