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Nanoscopic Insights to Proteins against Huntington’s Disease

Research team from various institutes in Academia Sinica report an amphiphilic peptide able to block protein aggregation in the pathogenesis of Huntington’s Disease.

Despite growing ageing populations in the past decades, effective therapeutic regimes for various age-related neurodegenerative disorders still remains an unmet medical need.

In January 2020, Dr. Joseph Huang Jen-Tse, an associate research fellow at the Institute of Chemistry in Academia Sinica, Dr. Tu Pang-Hsien, a former assistant research fellow at the Institute of Biomedical Science, and their research teams published their findings in Advanced Science. These findings demonstrated self-assembled amphiphilic peptide that can inhibit protein aggregation implicated in the pathogenesis of Huntington’s disease.

Current knowledge of Huntington’s disease (HD) indicates the oligomerization and aggregation of the mutant Huntingtin (mHtt) protein are closely related to HD proteinopathy. Due to the challenges in observing the dynamic aggregation and oligomerization of mHtt in vivo, the identification of potential drug targets are restricted.

By combing lifetime-based fluorescence microscopies and biophysical tools, Dr. Huang and Dr. Tu demonstrate the designed amphiphilic peptide, which targets the mHtt at an early stage, can perturb the oligomer assembly process nanoscopically, suppress the amyloid property of mHtt, and ameliorate mHtt-induced neurological damage in cell and mouse models.

Dr. Huang remarked, “While tracking the transient and subtle changes in protein conformational dynamics in vitro is feasible, observing the aforementioned phenomenon in live cells remains challenging. By establishing a combined biophotonic platform, we are the first to visualize not only the aggregation but also the oligomerization process perturbed by the amphiphilic peptide in live neuronal cells in real time.”

Additionally, the team discovered that the amphiphilic peptide is able to travel to the brain and rescue the memory deficit through intranasal administration.

Related patent to this collaborative and multidisciplinary study has been approved in Taiwan and under application in other countries. This study provides new insight into the design of a targeted therapeutic agent and creates a biophotonic platform for monitoring the oligomerization process in neurodegenerative diseases.

Dr. He Ruei-Yu is the first author in this study. The corresponding authors include Dr. Joseph Huang Jen-Tse, Dr. He Ruei-Yu, and Dr. Tu Pang-Hsien. Dr. Huang also appreciates the contributions from Dr. Chen Jen-Kun and Dr. Liao Yung-Feng from the Institute of Biomedical Engineering and Nanomedicine in National Health Research Institutes and the Institute of Cellular and Organismic Biology in Academia Sinica. [APBN]