Nuclear membrane protein SUN2 promotes replication of flaviviruses through modulating cytoskeleton reorganization mediated by NS1.

Cytoskeleton is extensively recruited by flaviviruses for their infection. In this study, we uncovered an essential role of a nuclear membrane protein, SAD1/UNC84 domain protein 2 (SUN2) linking cytoskeleton and nucleoskeleton in the flavivirus replication. CRISPR/Cas9-mediated knockout of SUN2, but not SUN1, significantly reduces the replication of Zika virus (ZIKV), dengue virus (DENV), and Japanese encephalitis virus (JEV). In contrast, SUN2 does not affect the infection of non-flaviviridae RNA viruses. All three regions of SUN2 are required for its proviral effect. Mechanistically, SUN2 facilitates rearrangement of cytoskeleton and formation of replication organelles induced by viral infection, and hence promotes viral RNA synthesis. SUN2 is required for the interaction between cytoskeleton actin and ZIKV nonstructural protein 1 (NS1). Expression of dominant negative Nesprin-1 and Nesprin-2, which connect SUN2 to cytoskeleton proteins, alleviates the interaction between actin and NS1 and reduces viral replication levels. In a neonatal mouse infection model, SUN2 knockout dramatically alleviates the in vivo ZIKV replication and development of neuropathology. This work elucidates that recruitment of cytoskeleton proteins by flavivirus is coordinated by nuclear membrane proteins SUN2 and Nesprins, providing evidence for a link between nuclear membrane proteins and flavivirus infection.

Emerging Roles of Meningeal Lymphatic Vessels in Alzheimer's Disease.

Meningeal lymphatic vessels (mLVs), the functional lymphatic system present in the meninges, are the key drainage route responsible for the clearance of molecules, immune cells, and cellular debris from the cerebrospinal fluid and interstitial fluid into deep cervical lymph nodes. Aging and ApoE4, the two most important risk factors for Alzheimer's disease (AD), induce mLV dysfunction, decrease cerebrospinal fluid influx and outflux, and exacerbate amyloid pathology and cognitive dysfunction. Dysfunction of mLVs results in the deposition of metabolic products, accelerates neuroinflammation, and promotes the release of pro-inflammatory cytokines in the brain. Thus, mLVs represent a novel therapeutic target for treating neurodegenerative and neuroinflammatory diseases. This review aims to summarize the structure and function of mLVs and to discuss the potential effect of aging and ApoE4 on mLV dysfunction, as well as their roles in the pathogenesis of AD.

Galectin-9/Tim-3 pathway mediates dopaminergic neurodegeneration in MPTP-induced mouse model of Parkinson's disease.

Galectin-9 (Gal-9) is a crucial immunoregulatory mediator in the central nervous system. Microglial activation and neuroinflammation play a key role in the degeneration of dopaminergic neurons in the substantia nigra (SN) in Parkinson's disease (PD). However, it remains unknown whether Gal-9 is involved in the pathogenesis of PD. We found that MPP+ treatment promoted the expression of Gal-9 and pro-inflammatory cytokines (IL-6, IL-1ß, TNF-α, and MIP-1α) in a concentration-dependent manner in BV2 cells. Gal-9 enhanced neurodegeneration and oxidative stress induced by MPP+ in SH-SY5Y cells and primary neurons. Importantly, deletion of Gal-9 or blockade of Tim-3 ameliorated microglial activation, reduced dopaminergic neuronal loss, and improved motor performance in an MPTP-induced mouse model of PD. These observations demonstrate a pathogenic role of the Gal-9/Tim-3 pathway in exacerbating microglial activation, neuroinflammation, oxidative stress, and dopaminergic neurodegeneration in the pathogenesis of PD.

Islet amyloid polypeptide cross-seeds tau and drives the neurofibrillary pathology in Alzheimer's disease.

BACKGROUND: The pathologic accumulation and aggregation of tau is a hallmark of tauopathies including Alzheimer's disease (AD). However, the molecular mechanisms mediating tau aggregation in AD remain elusive. The incidence of AD is increased in patients with type 2 diabetes (T2DM), which is characterized by the amyloid deposition of islet amyloid polypeptide (IAPP) in the pancreas. However, the molecular mechanisms bridging AD and T2DM remain unknown. METHODS: We first examined the presence of IAPP in the neurofibrillary tangles of AD patients. Then we tested the effect of IAPP on tau aggregation. The biochemical and biological characteristics of the IAPP-tau fibrils were tested in vitro. The seeding activity and neurotoxicity of the IAPP-tau fibrils were confirmed in cultured neurons. Lastly, the effect of IAPP on tau pathology and cognitive impairments was determined by injecting the IAPP-tau fibrils and IAPP fibrils into the hippocampus of tau P301S mice. RESULTS: We found that IAPP interacts with tau and accelerates the formation of a more toxic strain, which shows distinct morphology with enhanced seeding activity and neurotoxicity in vitro. Intrahippocampal injection of the IAPP-tau strain into the tau P301S transgenic mice substantially promoted the spreading of tau pathology and induced more severe synapse loss and cognitive deficits, when compared with tau fibrils. Furthermore, intracerebral injection of synthetic IAPP fibrils initiated tauopathy in the brain of tau P301S transgenic mice. CONCLUSIONS: These observations indicate that IAPP acts as a crucial mediator of tau pathology in AD, and provide a mechanistic explanation for the higher risk of AD in individuals with T2DM.