Biology subjects

Garcia, M. L.

Publications and source records attributed to Garcia, M. L..

3 recordsLinked to original sources

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↗

bioRxiv2023

Expanding the repertoire of the plant infecting ophioviruses

Ophioviruses (genus Ophiovirus, family Aspiviridae) are plant-infecting viruses with non-enveloped, filamentous, naked nucleocapsid virions. Members of genus Ophiovirus have a segmented single-stranded negative-sense RNA genome (ca. 11.3-12.5 kb), encompassing three or four linear segments. These segments encode in total four to seven proteins in sense and antisense orientation, both in the viral and complementary strands. The genus Ophiovirus includes seven species with viruses infecting both monocots and dicots, mostly trees, shrubs and some ornamentals. From a genomic perspective, as of today, there are complete genomes available for only four species. Here, by exploring large metatranscriptomics publicly available datasets, we report the identification and molecular characterization of 33 novel viruses with genetic and evolutionary cues of ophioviruses. Genetic distance and evolutionary insights suggest that all the detected viruses could correspond to members of novel species, which expand ca. 4.5-fold the current diversity of ophioviruses. The detected viruses increase the tentative host range of ophioviruses for the first time to mosses, liverwort and ferns. In addition, viruses were linked to several Asteraceae, Orchidaceae and Poaceae crops/ornamental plants. Phylogenetic analyses showed a novel clade of mosses, liverworts and fern ophioviruses, characterized by long branches suggesting still plenty unsampled hidden diversity within the genus. This study represents a significant expansion of genomics of ophioviruses, opening the grounds to future works on the molecular and evolutionary peculiarity of this virus genus.

microbiology↗