Biology subjects

Aliya, B.

Publications and source records attributed to Aliya, B..

4 recordsLinked to original sources

bioRxiv2026

Temporal RNA splicing dysregulation in a human multicellular model of C9orf72 ALS

Amyotrophic lateral sclerosis (ALS) is a complex and heterogenous disease, comprising of familial and sporadic forms, numerous genetic mutations, and a wide range of affected cell types and proposed dysregulated processes. While the usage of in vitro cell cultures, mouse models, and postmortem patient tissue have advanced our understanding of ALS disease mechanisms, the temporal progression of the disease and how early molecular changes evolve remain poorly understood. Here, we establish human spinal cord organoids (hSpO) derived from C9orf72 patient induced pluripotent stem cells (C9-ALS hiPSCs) as a platform to model longitudinal changes across the disease trajectory. We show that C9-ALS hSpO recapitulate hallmark C9orf72-related pathologies, increased cell death, and progressive neuronal dysfunction. We further identify RNA splicing dysregulation as an early and persistent feature of C9-ALS, with splicing signatures in hSpO closely mirroring those observed in postmortem patient tissue. Finally, prediction of RNA binding proteins (RBPs) that induce early splicing changes in C9-ALS reveals signatures consistent with a broad RBP network dysfunction. Together, this work establishes hSpO as an in vitro system for investigating early disease mechanisms of ALS in a human multicellular context and highlights dysregulated events that precede cell death.

neuroscience↗

bioRxiv2021

Comparison of neuromuscular junction dynamics following ischemic and aged skeletal muscle

Both aging and neuromuscular diseases lead to significant changes in the morphology and functionality of the neuromuscular synapse. Skeletal muscles display a remarkable regenerative capacity, however, are still susceptible to diseases of aging and peripheral nerve perturbations. In this study, we assessed how neuromuscular synapses differ in aged and injured skeletal muscle using an improved neuromuscular junction (NMJ) staining and imaging method. We found that both aged and ischemic skeletal muscle display Wallerian degeneration of the presynaptic motor axons and fragmentation of postsynaptic acetylcholine receptors (AChRs). Quantifiable measurements of various metrics of the NMJs provide a more concrete idea of the dynamics that are occurring in the muscle microenvironment. We questioned whether neuronal degradation precedes myofiber atrophy or vice versa. Previously, it was shown that a cellular crosstalk exists among the motor neurons, myofibers, vasculature, and mitochondria within the muscle microdomain. It is apparent that lack of blood flow to motor neurons in ischemic skeletal muscle disrupts the structure of NMJs, however it is unclear if the aging condition experiences similar dynamics. We demonstrated that both aged and ischemic skeletal muscle demonstrate similar patterns of degeneration, characterized by a smaller percentage overlap of presynaptic and postsynaptic sides, greater fragmentation of AChRs, and a smaller area of AChR clusters. Together, these results reveal high resolution, precise parallels between the aged and ischemic NMJs. Impact StatementThe goal of this study was to assess changes in presynaptic motor neurons and postsynaptic acetylcholine receptors following an ischemic injury model and compare this with an aging model. This was accomplished by characterizing key components of NMJ morphology, including overlap and size of the receptors. There is currently limited research investigating the cellular communication between skeletal muscle fibers and motor neurons. Additionally, there is limited work comparing neuromuscular remodeling in aged and young models. With the substantial prevalence of neuromuscular disorders, especially in the aging population, it is essential to understand nerve-muscle interactions in order to promote increased mobility and improved quality of life in both injury and aging models.

neuroscience↗

bioRxiv2020

Transplantation of muscle stem cell mitochondria rejuvenates the bioenergetic function of dystrophic muscle

Mitochondrial dysfunction has been implicated in various pathologies, including muscular dystrophies. During muscle regeneration, resident stem cells, also known as muscle satellite cells (MuSCs), undergo myogenic differentiation to form de novo myofibers or fuse to existing syncytia. Leveraging this cell-cell fusion process, we postulated that mitochondria stemming from MuSCs could be transferred to myofibers during muscle regeneration to remodel the mitochondrial network and restore bioenergetic function. Here, we report that dystrophic MuSCs manifest significant mitochondrial dysfunction and fuse with existing dystrophic myofibers to propagate mitochondrial dysfunction during muscle repair. We demonstrate that by transplanting healthy donor MuSCs into dystrophic host muscle, the mitochondrial network (reticulum) and bioenergetic function can be rejuvenated. Conversely, when bioenergetically-compromised donor MuSCs are transplanted, improvements in mitochondrial organization and bioenergetic function were ablated in the dystrophic recipient. Overall, these data reveal a unique role of muscle stem cells as an essential regulator of myofiber mitochondrial homeostasis and a potential therapeutic target against mitochondrial myopathies.

cell biology↗

bioRxiv2018

Critical Limb Ischemia Induces Remodeling of Skeletal Muscle Motor Unit and Myonuclear- and Mitochondrial-Domains

Critical limb ischemia, the most severe form of peripheral artery disease, leads to extensive damage and alterations in skeletal muscle homeostasis. Although recent developments towards revascularization therapies have been introduced, there has been limited research into treatments for ischemic myopathy. To elucidate the regenerative mechanism of the muscle stem cell and its niche components in response to ischemic insults, we explored interactions between the vasculature, motor neuron, muscle fiber, and the muscle stem cell. We first investigated changes in the neuromuscular junction and motor neuron innervation following a surgical hindlimb ischemia model of critical limb ischemia in mice. Along with previous findings that support remodeling of the neuromuscular junction, we report that ischemic injury also causes significant alterations to the myofiber through a muscle stem cell-mediated increase of myonuclei number per fiber, a concomitant decrease in myonuclear domain size, and an increase in relative mitochondrial content per myonucleus. These results indicate that as a regenerative response to critical limb ischemia, myofibers exhibit myonuclear expansion to allow enhanced transcriptional support and an increase in mitochondrial content for bioenergetic need of the energy-demanding tissue regeneration.

physiology↗