La enfermedad de Parkinson es una afección cerebral que provoca movimientos incontrolables o involuntarios.
El nanocuerpo también puede perforar células cerebrales resistentes.
El sistema inmunitario utiliza proteínas denominadas anticuerpos para detectar y atacar a los patógenos invasores. Se están investigando versiones en miniatura de anticuerpos, llamados nanocuerpos, compuestos naturales en la sangre de animales como llamas y tiburones, para tratar enfermedades autoinmunes y cáncer. Ahora, los científicos de Johns Hopkins Medicine han ayudado a crear un nanocuerpo que puede penetrar la dura capa externa de las células cerebrales y desenredar las proteínas deformes que causan trastornos como la enfermedad de Parkinson, la demencia con cuerpos de Lewy y otros problemas neurocognitivos.
La estructura de los grupos de alfa-sinucleína (a la izquierda) fue interrumpida por el nanocuerpo PFFNB2 (como se muestra a la derecha). Crédito: Xiaobo Mao
Investigadores de Johns Hopkins Medicine, bajo la dirección de Xiaobo Mao, Ph.D., e investigadores de la Universidad de Michigan, Ann Arbor, colaboraron en el estudio, que se publicó recientemente en la revista
An infographic describing nanobodies. Credit: Ayanna Tucker, Joshua Glenn, and Lauren Hines
The team made seven, similar types of nanobodies, known as PFFNBs, that could bind to alpha-synuclein clumps. Of the nanobodies they created, one — PFFNB2 — did the best job of glomming onto alpha-synuclein clumps and not single molecules, or monomers of alpha-synuclein. Monomer versions of alpha-synuclein are not harmful and may have important functions in brain cells. The researchers also needed to determine if the PFFNB2 nanobody could remain stable and work inside brain cells. The team found that in live mouse-brain cells and tissue, PFFNB2 was stable and showed a strong affinity to alpha-synuclein clumps rather than single alpha-synuclein monomers.
Additional tests in mice showed that the PFFNB2 nanobody cannot prevent alpha-synuclein from collecting into clumps, but it can disrupt and destabilize the structure of existing clumps.
“Strikingly, we induced PFFNB2 expression in the cortex, and it prevented alpha-synuclein clumps from spreading to the mouse brain’s cortex, the region responsible for cognition, movement, personality, and other high-order processes,” says Ramhari Kumbhar, Ph.D., the co-first author, a postdoctoral fellow at the Johns Hopkins University School of Medicine.
“The success of PFFNB2 in binding harmful alpha-synuclein clumps in increasingly complex environments indicates that the nanobody could be key to helping scientists study these diseases and eventually develop new treatments,” says Mao, associate professor of neurology.
Reference: “α-Synuclein fibril-specific nanobody reduces prion-like α-synuclein spreading in mice” by Yemima R. Butler, Yuqing Liu, Ramhari Kumbhar, Peiran Zhao, Kundlik Gadhave, Ning Wang, Yanmei Li, Xiaobo Mao, and Wenjing Wang, 19 July 2022, Nature Communications.
DOI: 10.1038/s41467-022-31787-2
The study was funded by the University of Michigan, the National Institutes of Health, the Parkinson’s Foundation, and the Maryland Stem Cell Research Foundation.
