Pickles Sarah R, Gonzalez Bejarano Jesus, Narayan Anand, Daughrity Lillian, Maroto Cidfuentes Candela, Reeves Madison M, Yue Mei, Castellanos Otero Paula, Estades Ayuso Virginia, Dunmore Judy, Song Yuping, Tong Jimei, DeTure Michael, Rawlinson Bailey, Castanedes-Casey Monica, Dulski Jaroslaw, Cerquera-Cleves Catalina, Zhang Yongjie, Josephs Keith A, Dickson Dennis W, Petrucelli Leonard, Wszolek Zbigniew K, Prudencio Mercedes
Department of Neuroscience, Mayo Clinic, Jacksonville, Florida, USA.
Neurobiology of Disease Graduate Program, Mayo Graduate School, Mayo Clinic College of Medicine, Jacksonville, Florida, USA.
Mov Disord. 2025 Apr;40(4):662-671. doi: 10.1002/mds.30104. Epub 2025 Jan 9.
Perry syndrome (PS) is a rare and fatal hereditary autosomal dominant neurodegenerative disorder caused by mutations in dynactin (DCTN1). PS brains accumulate inclusions positive for ubiquitin, transactive-response DNA-binding protein of 43 kDa (TDP-43), and to a lesser extent dynactin.
Little is known regarding the contributions of TDP-43, an RNA binding protein that represses cryptic exon inclusion, in PS. Therefore, we sought to identify the degree of TDP-43 dysfunction in two regions of PS brains.
We evaluated the levels of insoluble pTDP-43 and TDP-43-regulated cryptic RNAs and protein in the caudate nucleus and substantia nigra of 7 PS cases, 12 cases of frontotemporal lobar degeneration (FTLD) with TDP-43 pathology, and 11 cognitively healthy controls without TDP-43 pathology.
Insoluble pTDP-43 protein levels were detected in PS brains to a similar extent in the caudate nucleus and substantia nigra but lower than those in FTLD brains. The caudate nucleus of PS showed accumulation of eight TDP-43-regulated cryptic RNAs (ACTL6B, CAMK2B, STMN2, UNC13A, KCNQ2, ATG4B, GPSM2, and HDGFL2) and cryptic protein (HDGFL2) characteristic of FTLD. Conversely, only one cryptic target, UNC13A, reached significance in the substantia nigra despite similar pTDP-43 levels.
We detected TDP-43 cryptic RNAs and protein in PS caudate nucleus. Given the importance of cryptic exon biology in the development of biomarkers, and the identification of novel targets for therapeutic intervention, it is imperative we understand the consequences of TDP-43 dysfunction across different brain regions and determine the targets that are specific and common to TDP-43 proteinopathies. © 2025 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.
佩里综合征（PS）是一种罕见的致命性常染色体显性遗传神经退行性疾病，由动力蛋白（DCTN1）突变引起。PS患者的大脑中会积累泛素、43 kDa反式激活反应DNA结合蛋白（TDP - 43）阳性的包涵体，动力蛋白的积累程度相对较轻。
关于TDP - 43（一种抑制隐蔽外显子包含的RNA结合蛋白）在PS中的作用，目前所知甚少。因此，我们试图确定PS患者大脑两个区域中TDP - 43功能障碍的程度。
我们评估了7例PS患者、12例伴有TDP - 43病理改变的额颞叶痴呆（FTLD）患者以及11例无TDP - 43病理改变的认知健康对照者尾状核和黑质中不溶性磷酸化TDP - 43（pTDP - 43）的水平、TDP - 43调控的隐蔽RNA和蛋白质水平。
在PS患者的大脑中，尾状核和黑质中均可检测到不溶性pTDP - 43蛋白水平，且程度相似，但低于FTLD患者大脑中的水平。PS患者的尾状核显示出8种TDP - 43调控的隐蔽RNA（ACTL6B、CAMK2B、STMN2、UNC13A、KCNQ2、ATG4B、GPSM2和HDGFL2）以及FTLD特征性的隐蔽蛋白（HDGFL2）的积累。相反，尽管pTDP - 43水平相似，但在黑质中只有一个隐蔽靶点UNC13A达到显著水平。
我们在PS患者的尾状核中检测到了TDP - 43隐蔽RNA和蛋白质。鉴于隐蔽外显子生物学在生物标志物开发中的重要性以及确定治疗干预的新靶点，我们必须了解TDP - 43功能障碍在不同脑区的后果，并确定TDP - 43蛋白病特有的和共有的靶点。© 2025作者。《运动障碍》由Wiley Periodicals LLC代表国际帕金森和运动障碍协会出版。
