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    Rilmenidine promotes MTOR-independent autophagy in the mutant SOD1 mouse model of amyotrophic lateral sclerosis without slowing disease progression

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    Author
    Perera, ND; Sheean, RK; Lau, CL; Shin, YS; Beart, PM; Horne, MK; Turner, BJ
    Date
    2018-01-01
    Source Title
    Autophagy
    Publisher
    TAYLOR & FRANCIS INC
    University of Melbourne Author/s
    Turner, Bradley; Beart, Philip; Perera, Pannilage; Sheean, Rebecca; Lau, Chew Ling; Shin, Yea Seul; Horne, Malcolm
    Affiliation
    Florey Department of Neuroscience and Mental Health
    Anatomy and Neuroscience
    Metadata
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    Document Type
    Journal Article
    Citations
    Perera, N. D., Sheean, R. K., Lau, C. L., Shin, Y. S., Beart, P. M., Horne, M. K. & Turner, B. J. (2018). Rilmenidine promotes MTOR-independent autophagy in the mutant SOD1 mouse model of amyotrophic lateral sclerosis without slowing disease progression. AUTOPHAGY, 14 (3), pp.534-551. https://doi.org/10.1080/15548627.2017.1385674.
    Access Status
    Open Access
    URI
    http://hdl.handle.net/11343/257156
    DOI
    10.1080/15548627.2017.1385674
    Abstract
    Macroautophagy/autophagy is the main intracellular catabolic pathway in neurons that eliminates misfolded proteins, aggregates and damaged organelles associated with ageing and neurodegeneration. Autophagy is regulated by both MTOR-dependent and -independent pathways. There is increasing evidence that autophagy is compromised in neurodegenerative disorders, which may contribute to cytoplasmic sequestration of aggregation-prone and toxic proteins in neurons. Genetic or pharmacological modulation of autophagy to promote clearance of misfolded proteins may be a promising therapeutic avenue for these disorders. Here, we demonstrate robust autophagy induction in motor neuronal cells expressing SOD1 or TARDBP/TDP-43 mutants linked to amyotrophic lateral sclerosis (ALS). Treatment of these cells with rilmenidine, an anti-hypertensive agent and imidazoline-1 receptor agonist that induces autophagy, promoted autophagic clearance of mutant SOD1 and efficient mitophagy. Rilmenidine administration to mutant SOD1G93A mice upregulated autophagy and mitophagy in spinal cord, leading to reduced soluble mutant SOD1 levels. Importantly, rilmenidine increased autophagosome abundance in motor neurons of SOD1G93A mice, suggesting a direct action on target cells. Despite robust induction of autophagy in vivo, rilmenidine worsened motor neuron degeneration and symptom progression in SOD1G93A mice. These effects were associated with increased accumulation and aggregation of insoluble and misfolded SOD1 species outside the autophagy pathway, and severe mitochondrial depletion in motor neurons of rilmenidine-treated mice. These findings suggest that rilmenidine treatment may drive disease progression and neurodegeneration in this mouse model due to excessive mitophagy, implying that alternative strategies to beneficially stimulate autophagy are warranted in ALS.

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