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MINI REVIEW article

Front. Cell. Neurosci.

Sec. Non-Neuronal Cells

Volume 19 - 2025 | doi: 10.3389/fncel.2025.1553658

This article is part of the Research Topic Non-Neuronal Cells in Neurodegenerative Diseases and Psychiatric Disorders View all 8 articles

Role of Glia Cells in Motor Neuron Degeneration in Hereditary Spastic Paraplegias

Provisionally accepted
  • 1 University of Illinois College of Medicine Rockford, Rockford, United States
  • 2 University of Illinois Chicago, Chicago, United States

The final, formatted version of the article will be published soon.

    This review provides a comprehensive overview of hereditary spastic paraplegias (HSPs) and summarizes the recent progress on the role of glial cells in the pathogenesis of HSPs. HSPs are a heterogeneous group of neurogenetic diseases characterized by axonal degeneration of cortical motor neurons, leading to muscle weakness and atrophy. Though the contribution of glial cells, especially astrocytes, to the progression of other motor neuron diseases like amyotrophic lateral sclerosis (ALS) is well documented, the role of glial cells and the interaction between neurons and astrocytes in HSP remained unknown until recently. Using human pluripotent stem cell-based models of HSPs, a study reported impaired lipid metabolisms and reduced size of lipid droplets in HSP astrocytes. Moreover, targeting lipid dysfunction in astrocytes rescues axonal degeneration of HSP cortical neurons, demonstrating a non-cell-autonomous mechanism in axonal deficits of HSP neurons. In addition to astrocytes, recent studies revealed dysfunctions in HSP patient pluripotent stem cell-derived microglial cells. Increased microgliosis and pro-inflammation factors were also observed in HSP patients' samples, pointing to an exciting role of innate immunity and microglia in HSP. Building upon these recent studies, further investigation of the detailed molecular mechanism and the interplay between glial cell dysfunction and neuronal degeneration in HSP by combining human stem cell models, animal models, and patient samples will open avenues for identifying new therapeutic targets and strategies for HSP.

    Keywords: Axonal degeneration, Motor Neurons, Astrocytes, Microglia, Lipid dysfunction, neuroinflammation Article type: Mini-Review

    Received: 31 Dec 2024; Accepted: 25 Mar 2025.

    Copyright: © 2025 Vijayaraghavan, Murali, Thakur and Li. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

    * Correspondence: Xue-Jun Li, University of Illinois Chicago, Chicago, United States

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