Veverová Kateřina, Katonová Alžběta, Horáková Hana, Laczó Jan, Angelucci Francesco, Hort Jakub, Lautrup Sofie, Fang Evandro Fei, Vyhnálek Martin
Memory Clinic, Department of Neurology, 2nd Faculty of Medicine, Charles University and Motol University Hospital, V Úvalu 84, Prague 5, 150 06, Czech Republic.
Department of Clinical Molecular Biology, University of Oslo and Akershus University Hospital, Lørenskog, 1478, Norway.
Acta Neuropathol Commun. 2025 Feb 20;13(1):37. doi: 10.1186/s40478-025-01954-9.
Maintaining cellular homeostasis by removing damaged and senescent mitochondria, a process termed mitophagy, is crucial in preventing Alzheimer's disease (AD) and represents a promising therapeutic target. Our previous research revealed altered mitophagy biomarkers, such as increased CSF and serum PINK1 and serum BNIP3L and decreased serum TFEB levels, indicating impaired autophagy-lysosomal degradation in the AD continuum. However, the role of autophagy/mitophagy in frontotemporal lobar degeneration (FTLD) remains unclear. This study investigated the biomarkers of autophagy/mitophagy and lysosomal biogenesis (PINK1, ULK1, BNIP3L, and TFEB) in biofluids (CSF and serum) from 308 biomarker-defined individuals across the FTLD continuum (FTLD-dementia, n = 29; FTLD-MCI, n = 33) and compared them with those across the AD continuum (MCI-AD, n = 100; AD-dementia, n = 100) and cognitively unimpaired (CU) controls (n = 46) recruited from Czech Brain Aging Study. Additionally, we compared the mitophagy biomarkers across different FTLD clinical subtypes (frontal, semantic and nonfluent variant) with CU, and explored the association between mitophagy biomarkers and clinical phenotypes of FTLD (biomarkers of tau, biomarkers of neurodegeneration, cognition and ATN profile).Our findings indicated a significantly lower CSF PINK1 and ULK1 levels in FTLD compared to AD, with FTLD dementia showing particularly low CSF PINK1 levels compared to AD-dementia. Conversely, CSF ULK1 levels were higher in FTLD-MCI compared to AD-dementia. Serum analyses revealed lower PINK1 and higher TFEB levels in FTLD dementia compared to AD dementia. This study provides compelling evidence of distinct alterations in autophagy/mitophagy biomarkers between FTLD and AD, indicating that these neurodegenerative diseases may affect the cellular waste disposal system through different pathways. This is the first study to explore mitophagy biomarkers in human CSF and serum in FTLD, opening avenues for further research and potential clinical applications.
通过清除受损和衰老的线粒体来维持细胞内稳态，这一过程称为线粒体自噬，对预防阿尔茨海默病（AD）至关重要，并且是一个有前景的治疗靶点。我们之前的研究揭示了线粒体自噬生物标志物的改变，如脑脊液（CSF）和血清中PINK1增加、血清中BNIP3L增加以及血清中TFEB水平降低，这表明在AD连续体中自噬-溶酶体降解受损。然而，自噬/线粒体自噬在额颞叶痴呆（FTLD）中的作用仍不清楚。本研究调查了308名生物标志物定义的个体（来自FTLD连续体，包括FTLD痴呆，n = 29；FTLD轻度认知障碍，n = 33）的生物流体（CSF和血清）中自噬/线粒体自噬和溶酶体生物发生的生物标志物（PINK1、ULK1、BNIP3L和TFEB），并将其与来自捷克脑老化研究的AD连续体（MCI-AD，n = 100；AD痴呆，n = 100）和认知未受损（CU）对照（n = 46）中的生物标志物进行比较。此外，我们比较了不同FTLD临床亚型（额叶、语义和非流利变异型）与CU之间的线粒体自噬生物标志物，并探讨了线粒体自噬生物标志物与FTLD临床表型（tau生物标志物、神经退行性变生物标志物、认知和ATN特征）之间的关联。我们的研究结果表明，与AD相比，FTLD患者的CSF中PINK1和ULK1水平显著降低，与AD痴呆相比，FTLD痴呆患者的CSF中PINK1水平尤其低。相反，与AD痴呆相比，FTLD-MCI患者的CSF中ULK1水平更高。血清分析显示，与AD痴呆相比，FTLD痴呆患者的PINK1水平更低，TFEB水平更高。本研究提供了令人信服的证据，表明FTLD和AD之间自噬/线粒体自噬生物标志物存在明显差异，这表明这些神经退行性疾病可能通过不同途径影响细胞废物处理系统。这是第一项在FTLD患者的人体CSF和血清中探索线粒体自噬生物标志物的研究，为进一步研究和潜在临床应用开辟了道路。
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