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<p>The accumulation of α-synuclein within Lewy bodies is a critical factor in the pathogenesis of Parkinson’s disease, with potential implications for axonal transport deficits. Activated asparagine endopeptidase enzymatically cleaves α-synuclein and tau, resulting in the formation of α-SynN103 and tauN368, which are markedly elevated in the brains with Parkinson’s disease. In this study, rats received intrastriatal injections of 15 µg of preformed α-SynN103 and tauN368 fibrils, and their behaviors were evaluated after a 2-month period. Subsequent analyses investigated alterations in axonal transport and the underlying molecular mechanisms. Our findings indicated that preformed fibrils reduced kinesin levels and excessively activated the AMPK and p38 MAPK, thereby compromising the function of kinesin and dynein in axonal transport. Pharmacological inhibition of AMPK and p38 MAPK ameliorated these dysfunctions in rat models, which identified Compound C and SB203580 as potent inhibitors, offering evidence for early interventions of Parkinson’s disease.</p><p></p>

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Disruption of axonal transport in Parkinson’s disease: the role of pathological α-Syn and AMPK/p38 MAPK signaling

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年5月6日

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  • Xiaoman Yang,
  • Zhuoran Ma,
  • Piaopiao Lian,
  • Yi Wu,
  • Ke Liu,
  • Zhaoyuan Zhang,
  • Zhicheng Tang,
  • Yan Xu,
  • Xuebing Cao

摘要

The accumulation of α-synuclein within Lewy bodies is a critical factor in the pathogenesis of Parkinson’s disease, with potential implications for axonal transport deficits. Activated asparagine endopeptidase enzymatically cleaves α-synuclein and tau, resulting in the formation of α-SynN103 and tauN368, which are markedly elevated in the brains with Parkinson’s disease. In this study, rats received intrastriatal injections of 15 µg of preformed α-SynN103 and tauN368 fibrils, and their behaviors were evaluated after a 2-month period. Subsequent analyses investigated alterations in axonal transport and the underlying molecular mechanisms. Our findings indicated that preformed fibrils reduced kinesin levels and excessively activated the AMPK and p38 MAPK, thereby compromising the function of kinesin and dynein in axonal transport. Pharmacological inhibition of AMPK and p38 MAPK ameliorated these dysfunctions in rat models, which identified Compound C and SB203580 as potent inhibitors, offering evidence for early interventions of Parkinson’s disease.