Krzystek Thomas J, Gunawardena Shermali
Department of Biological Sciences, The State University of New York at Buffalo, Buffalo, New York, USA.
Autophagy Rep. 2025 Jun 2;4(1):2472450. doi: 10.1080/27694127.2025.2472450. eCollection 2025.
Neurons, as post-mitotic and long-lived cells, rely heavily on autophagy to maintain cellular homoeostasis and ensure proper function. Huntingtin (HTT), a protein central to Huntington's disease (HD), has emerged as a putative multifunctional regulator within the neuronal autophagy-lysosome pathway. This review explores normal HTT's multifaceted role in neuronal autophagy, from its potential involvement in autophagy induction, its capacity to influence cargo recognition and autophagosome formation, and its contribution to autophagosome-lysosome fusion and transport. We also discuss the unique challenges that neurons face in maintaining proteostasis through autophagy, emphasising the need for specialised mechanisms like axonal transport of autophagosomes and distinct regulatory pathways. Furthermore, we highlight the spatial and temporal regulation of neuronal autophagy, particularly in the context of ageing and neuronal maturation, underscoring the importance of understanding HTT's role in different neuronal states. By elucidating the intricate relationship between HTT and neuronal autophagy, this review aims to shed light on specific mechanisms of action in autophagy that can be disrupted in neurodegenerative diseases including HD.
神经元作为终末有丝分裂且寿命较长的细胞，在很大程度上依赖自噬来维持细胞内稳态并确保正常功能。亨廷顿蛋白（HTT）是亨廷顿舞蹈病（HD）的关键蛋白，已成为神经元自噬 - 溶酶体途径中一种假定的多功能调节因子。本综述探讨了正常HTT在神经元自噬中的多方面作用，包括其在自噬诱导中的潜在参与、影响货物识别和自噬体形成的能力，以及对自噬体 - 溶酶体融合和运输的贡献。我们还讨论了神经元在通过自噬维持蛋白质稳态方面面临的独特挑战，强调了诸如自噬体轴突运输等特殊机制和不同调节途径的必要性。此外，我们强调了神经元自噬的时空调节，特别是在衰老和神经元成熟的背景下，突出了理解HTT在不同神经元状态下作用的重要性。通过阐明HTT与神经元自噬之间的复杂关系，本综述旨在揭示自噬中可能在包括HD在内的神经退行性疾病中被破坏的具体作用机制。
