期刊
AUTOPHAGY
卷 14, 期 3, 页码 534-551出版社
TAYLOR & FRANCIS INC
DOI: 10.1080/15548627.2017.1385674
关键词
ALS; autophagy; motor neuron; rilmenidine; SOD1; TARDBP
类别
资金
- Australian National Health and Medical Research Council [1104299, 1104295]
- Stafford Fox Medical Research Foundation
- MND Research Institute of Australia (Susie Harris Memorial Fund)
- MND Research Institute of Australia (Zo-ee MND Research Grants)
- Bethlehem Griffiths Research Foundation
- Cavalier Courage MND Research Grant
- Melbourne Support Grant Research Scheme
- Inner Wheel Club of Pakenham
- Operational Infrastructure Support Grant
- Australian Postgraduate Award Scholarship
- Victorian Government
- National Health and Medical Research Council of Australia [1104295, 1104299] Funding Source: NHMRC
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 SOD1(G93A) mice upregulated autophagy and mitophagy in spinal cord, leading to reduced soluble mutant SOD1 levels. Importantly, rilmenidine increased autophagosome abundance in motor neurons of SOD1(G93A) mice, suggesting a direct action on target cells. Despite robust induction of autophagy in vivo, rilmenidine worsened motor neuron degeneration and symptom progression in SOD1(G93A) 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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