Biology subjects

Lorson, C. L.

Publications and source records attributed to Lorson, C. L..

5 recordsLinked to original sources

bioRxiv2025

The Ighmbp2-R604X mouse recapitulates the severe SMARD1 clinical symptoms of aspiration, respiratory and feeding deficits

Spinal muscular atrophy with respiratory distress type 1 (SMARD1) and Charcot Marie Tooth type 2S (CMT2S) are due to mutations in immunoglobulin mu binding protein two (IGHMBP2). We generated the Ighmbp2-R604X mouse (R605X-humans) to understand how alterations in IGHMBP2 function impact disease pathology. The IGHMBP2-R605X mutation is associated with patients with SMARD1 or CMT2S. The impact of this mutation is substantial, Ighmbp2R604X/R604X mice have a decreased lifespan (6 days) and weight, and failure to thrive consistent with SMARD1 symptoms. Significant respiratory changes were present along with disease pathology of the phrenic nerve and diaphragm muscle fibers. Ighmbp2R604X/R604X mice also presented with signs of milk aspiration and lung pathology. Interestingly, Ighmbp2R604X/R604X mice were born with visible milk spots, but demonstrated reduction of the milk spot by P3, indicating deficits in suckling. Alterations in hindlimb electrophysiology were consistent with the sciatic nerve, hindlimb neuromuscular junction and muscle pathology. Injection of the ssAAV9-WT-IGHMBP2 vector extended Ighmbp2R604X/R604X survival a few days, due to reduced expression of the vector before death ensued. Ighmbp2R604X/R604X phenotypes are consistent with the most severe SMARD1 clinical symptoms and for the first time a Ighmbp2 mouse model demonstrates that milk aspiration and loss of the ability to suckle impact survival. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=148 SRC="FIGDIR/small/672633v1_ufig1.gif" ALT="Figure 1"> View larger version (39K): org.highwire.dtl.DTLVardef@e783b0org.highwire.dtl.DTLVardef@176cea5org.highwire.dtl.DTLVardef@f8b570org.highwire.dtl.DTLVardef@4fea4f_HPS_FORMAT_FIGEXP M_FIG C_FIG

neuroscience↗

bioRxiv2025

Novel neurofilament light (Nefl) E397K mouse models of Charcot-Marie-Tooth type 2E (CMT2E) present early and chronic axonal neuropathy

Charcot-Marie-Tooth (CMT) is the most common hereditary peripheral neuropathy with an incidence of 1:2,500. CMT2 clinical symptoms include distal muscle weakness and atrophy, sensory loss, toe and foot deformities, with some patients presenting with reduced nerve conduction velocity. Mutations in the neurofilament light chain (NEFL) gene result in a specific form of CMT2 disease, CMT2E. NEFL encodes the protein, NF-L, one of the core intermediate filament proteins that contribute to the maintenance and stability of the axonal cytoskeleton. To better understand the underlying biology of CMT2E disease and advance the development of therapeutics, we generated a Nefl+/E397K mouse model. While the Nefl+/E397K mutation is inherited in a dominant manner, we also characterized NeflE397K/E397K mice to determine whether disease onset, progression or severity would be impacted. Consistent with CMT2E, lifespan was not altered in these novel mouse models. A longitudinal electrophysiology study demonstrated significant in vivo functional abnormalities as early as P21 in distal latency, compound muscle action potential (CMAP) amplitude and negative area. A significant reduction in the sciatic nerve axon area, diameter, and G-ratio was also present as early as P21. Evidence of axon sprouting was observed with disease progression. Through the twelve months measured, disease became more evident in all assessments. Collectively, these results demonstrate an early and robust in vivo electrophysiological phenotype and axonal pathology, making Nefl+/E397K and NeflE397K/E397Kmice ideal for the evaluation of therapeutic approaches.

neuroscience↗

bioRxiv2025

The NeflE397K mouse model demonstrates muscle pathology and motor function deficits consistent with CMT2E

Charcot-Marie-Tooth (CMT) disease affects approximately 1 in 2,500 people and represents a heterogeneous group of inherited peripheral neuropathies characterized by progressive motor and sensory dysfunction. CMT type 2E is a result of mutations in the neurofilament light (NEFL) gene with predominantly autosomal dominant inheritance, often presenting with a progressive neuropathy with distal muscle weakness, sensory loss, gait disturbances, foot deformities, reduced nerve conduction velocity (NCV) without demyelination and typically reduced compound muscle action potential (CMAP) amplitude values. Several Nefl mouse models exist that either alter the mouse Nefl gene or overexpress a mutated human NEFL transgene, each recapitulating various aspects of CMT2E disease. We generated the orthologous NEFLE396K mutation in the mouse C57BL/6 background, NeflE397K. In a separate report, we extensively characterized the electrophysiology deficits and axon pathology in NeflE397K mice. In this manuscript, we report our characterization of NeflE397K motor function deficits, muscle pathology and changes in breathing Nefl+/E397K and NeflE397K/E397K mice demonstrated progressive motor coordination deficits and muscle weakness through the twelve months of age analyzed, consistent with our electrophysiology findings. Additionally, Nefl+/E397K and NeflE397K/E397K mice showed alterations in muscle fiber area, diameter and composition as disease developed. Lastly, Nefl mutant mice showed increased number of apneas under normoxia conditions and increased erratic breathing as well as tidal volume under respiratory challenge conditions. NeflE397K/E397K mice phenotypes and pathology were consistently more severe than Nefl+/E397K mice. Collectively, these novel CMT2E models present with a clinically relevant phenotype and make it an ideal model for the evaluation of therapeutics.

neuroscience↗

bioRxiv2021

Discovery and in-vitro evaluation of potent SARS-CoV-2 entry inhibitors

SARS-CoV-2 infection initiates with the attachment of spike protein to the ACE2 receptor. While vaccines have been developed, no SARS-CoV-2 specific small molecule inhibitors have been approved. Herein, utilizing the crystal structure of the ACE2/Spike receptor binding domain (S-RBD) complex in computer-aided drug design (CADD) approach, we docked [~]8 million compounds within the pockets residing at S-RBD/ACE2 interface. Five best hits depending on the docking score, were selected and tested for their in vitro efficacy to block SARS-CoV-2 replication. Of these, two compounds (MU-UNMC-1 and MU-UNMC-2) blocked SARS-CoV-2 replication at sub-micromolar IC50 in human bronchial epithelial cells (UNCN1T) and Vero cells. Furthermore, MU-UNMC-2 was highly potent in blocking the virus entry by using pseudoviral particles expressing SARS-CoV-2 spike. Finally, we found that MU-UNMC-2 is highly synergistic with remdesivir (RDV), suggesting that minimal amounts are needed when used in combination with RDV, and has the potential to develop as a potential entry inhibitor for COVID-19.

molecular biology↗

bioRxiv2021

Factors Associated with Emerging and Re-emerging of SARS-CoV-2 Variants

Global spread of Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) has triggered unprecedented scientific efforts, as well as containment and treatment measures. Despite these efforts, SARS-CoV-2 infections remain unmanageable in some parts of the world. Due to inherent mutability of RNA viruses, it is not surprising that the SARS-CoV-2 genome has been continuously evolving since its emergence. Recently, four functionally distinct variants, B.1.1.7, B.1.351, P.1 and CAL.20C, have been identified, and they appear to more infectious and transmissible than the original (Wuhan-Hu-1) virus. Here we provide evidence based upon a combination of bioinformatics and structural approaches that can explain the higher infectivity of the new variants. Our results show that the greater infectivity of SARS-CoV-2 than SARS-CoV can be attributed to a combination of several factors, including alternate receptors. Additionally, we show that new SARS-CoV-2 variants emerged in the background of D614G in Spike protein and P323L in RNA polymerase. The correlation analyses showed that all mutations in specific variants did not evolve simultaneously. Instead, some mutations evolved most likely to compensate for the viral fitness.

bioinformatics↗