Blood levels of neurofilament light are associated with disease progression in a mouse model of spinocerebellar ataxia type 3.
Blood levels of neurofilament light are associated with disease progression in a mouse model of spinocerebellar ataxia type 3.
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DOI：
10.1242/dmm.050144
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发表时间：
2023-09-01
影响因子：
4.3
通讯作者：
McLoughlin HS
中科院分区：
文献类型：
--
作者：
Mengel D;Wellik IG;Schuster KH;Jarrah SI;Wacker M;Ashraf NS;Öz G;Synofzik M;Costa MDC;McLoughlin HS
生物体液中神经丝光（NfL； NEFL）蛋白的增加反映了神经退行性疾病，并作为神经退行性疾病的生物标志物而受到关注。脊髓小脑性共济失调3型（SCA3）是最常见的显性遗传性共济失调，患者在出现症状时外周血中NfL呈进行性升高，并且NfL在进一步的病程中保持稳定升高。然而，进行性NfL变化尚未在相关的临床前SCA3动物模型中得到验证，这阻碍了其在治疗开发过程中作为生物标志物的应用。我们使用超灵敏单分子阵列（Simoa）在SCA3模型YACQ84小鼠中测量血液NfL与疾病进展的关系，评估其与疾病严重程度指标的关系，包括年龄、CAG重复序列大小和磁共振波谱。YACQ84小鼠表现出血浆NfL增加，同时伴有共济失调相关的运动缺陷，以及血清NfL增加，这与先前建立的神经代谢物异常相关，这是SCA3患者疾病的两个相关指标。我们的研究结果表明，在临床前YACQ84小鼠中，NfL的进展增加，进一步支持了血液NfL作为周围神经变性生物标志物的实用性，并为SCA3发病机制的不同测量提供了一致的时间线。摘要：脊髓小脑性失调3型模型YACQ84小鼠外周血显示神经元特异性NfL增加，与疾病进展直接相关，为临床前治疗研究提供了一种生物标志物。
Increased neurofilament light (NfL; NEFL) protein in biofluids is reflective of neurodegeneration and has gained interest as a biomarker across neurodegenerative diseases. In spinocerebellar ataxia type 3 (SCA3), the most common dominantly inherited ataxia, patients exhibit progressive NfL increases in peripheral blood when becoming symptomatic, and NfL remains stably elevated throughout further disease course. However, progressive NfL changes are not yet validated in relevant preclinical SCA3 animal models, hindering its application as a biomarker during therapeutic development. We used ultra-sensitive single-molecule array (Simoa) to measure blood NfL over disease progression in YACQ84 mice, a model of SCA3, assessing relationships with measures of disease severity including age, CAG repeat size and magnetic resonance spectroscopy. YACQ84 mice exhibited plasma NfL increases that were concomitant with ataxia-related motor deficits as well as increased serum NfL, which correlated with previously established neurometabolite abnormalities, two relevant measures of disease in patients with SCA3. Our findings establish the progression of NfL increases in the preclinical YACQ84 mouse, further supporting the utility of blood NfL as a peripheral neurodegeneration biomarker and informing on coinciding timelines of different measures of SCA3 pathogenesis. Summary: Peripheral blood of YACQ84 mice, a model of spinocerebellar ataxia type 3, exhibits increased neuronal-specific NfL, directly associated with disease progression, providing a biomarker to interrogate in preclinical therapeutic studies.
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影响因子：
5.1
作者：
Garcia-Moreno, Hector;Prudencio, Mercedes;Thomas-Black, Gilbert;Solanky, Nita;Jansen-West, Karen R.;Hanna AL-Shaikh, Rana;Heslegrave, Amanda;Zetterberg, Henrik;Santana, Magda M.;Pereira de Almeida, Luis;Vasconcelos-Ferreira, Ana;Januario, Cristina;Infante, Jon;Faber, Jennifer;Klockgether, Thomas;Reetz, Kathrin;Raposo, Mafalda;Ferreira, Ana F.;Lima, Manuela;Schols, Ludger;Synofzik, Matthis;Hubener-Schmid, Jeannette;Puschmann, Andreas;Gorcenco, Sorina;Wszolek, Zbigniew K.;Petrucelli, Leonard;Giunti, Paola
通讯作者：
Giunti, Paola
影响因子：
9.9
作者：
Johnson EB;Byrne LM;Gregory S;Rodrigues FB;Blennow K;Durr A;Leavitt BR;Roos RA;Zetterberg H;Tabrizi SJ;Scahill RI;Wild EJ;TRACK-HD Study Group
通讯作者：
TRACK-HD Study Group
影响因子：
11.2
作者：
Chandrasekaran, Jayashree;Petit, Emilien;Oz, Gulin
通讯作者：
Oz, Gulin
影响因子：
5.1
作者：
Haas E;Incebacak RD;Hentrich T;Huridou C;Schmidt T;Casadei N;Maringer Y;Bahl C;Zimmermann F;Mills JD;Aronica E;Riess O;Schulze-Hentrich JM;Hübener-Schmid J
通讯作者：
Hübener-Schmid J
影响因子：
30.8
作者：
KAWAGUCHI, Y;OKAMOTO, T;KAKIZUKA, A
通讯作者：
KAKIZUKA, A