Huashan Hospital Team Discovers Novel Therapeutic Target for Parkinson's Disease

Background

Parkinson's disease is the second most common neurodegenerative disorder after Alzheimer's disease and affects millions of people worldwide. Pathological forms of the protein α-synuclein accumulate in neurons and spread between cells, contributing to the progressive loss of dopamine-producing neurons. This leads to motor symptoms such as tremor, rigidity and bradykinesia, as well as non-motor symptoms. Existing treatments mainly manage symptoms but do not halt or slow the underlying disease progression. Researchers have long sought to understand the precise mechanisms of α-synuclein fibril uptake and transmission between neurons to develop disease-modifying therapies.

What was achieved

A research team led by Yu Jintai from Huashan Hospital Affiliated to Fudan University has identified FAM171A2 as a critical protein involved in the intercellular transmission of pathological α-synuclein. The findings were published in the journal Science on February 21, 2025, in a paper titled 'Neuronal FAM171A2 mediates α-synuclein fibril uptake and drives Parkinson’s disease' (Vol 387, Issue 6736, pp. 892-900, DOI: 10.1126/science.adp3645). First author Kai-Min Wu and colleagues determined that FAM171A2, previously an unstudied PD risk gene identified through genome-wide association studies, functions as the neuronal receptor for α-synuclein fibrils. The team also used AI-assisted virtual screening of more than 7,000 small molecule compounds to identify bemcentinib as a candidate that blocks the FAM171A2–α-synuclein fibril interaction.

Experiments in cellular models, in vitro binding assays and mice demonstrated protective effects from reducing FAM171A2 or inhibiting the interaction. The study involved five years of integrated clinical and basic research with collaborators including Peng Yuan and Cong Liu. The team has applied for an international patent targeting FAM171A2 for treating Parkinson's disease and plans further preclinical development of small molecules, antibodies and gene therapy approaches.

How it works

Pathological α-synuclein proteins misfold and aggregate into fibrils that can transfer from one neuron to another in a prion-like fashion. Once inside a healthy neuron, these fibrils act as templates, causing normal α-synuclein to misfold and aggregate, spreading the pathology and leading to neuron dysfunction and death. The Huashan team discovered that the protein FAM171A2 on the neuron cell membrane acts like a selective gate. Its extracellular domain 1 binds with high specificity—more than 1,000 times greater for fibrils than for non-pathological monomers—to the C-terminus of α-synuclein fibrils through electrostatic interactions. This binding triggers endocytosis, internalizing the fibrils into the neuron.

In patient brain samples, higher levels of FAM171A2 were associated with greater α-synuclein pathology. Reducing FAM171A2 specifically in neurons in transgenic mouse models limited the spread, reduced neurotoxicity and controlled Parkinson-like symptoms. The small molecule bemcentinib interferes with this binding, preventing fibril uptake by dopaminergic neurons in laboratory tests and animal models.

What it means for international patients

This research provides a new target for potential therapies aimed at intervening early to block the spread of pathology in Parkinson's disease, before extensive neuron loss occurs. It remains at the preclinical stage, with further work needed to advance candidate compounds toward clinical application. Huashan Hospital operates an International Medical Center established in 1989, one of the earliest such facilities in China. It has provided services to patients from more than 100 countries and regions, with dedicated facilities including independent consultation rooms, VIP suites and support in languages such as English, Japanese, French, German and Korean. The center uses a dedicated physician coordination model for full-cycle care with specialists across departments including neurology.

International patients considering neurological care at the hospital for Parkinson's disease, including symptom management or specialist consultations, should contact the International Medical Center directly to confirm current available services, eligibility and any ongoing research programs or clinical options. Availability and suitability of any approaches related to this research must be verified with the hospital.

About the hospital

Huashan Hospital Affiliated to Fudan University is located in Shanghai. Founded in 1907, it is a Grade 3A tertiary public hospital affiliated with Fudan University Shanghai Medical College and serves as a core unit of the National Center for Neurological Diseases. It is recognized for leadership in neurology and neurosurgery, with additional national strengths in infectious diseases, dermatology and hand surgery. The hospital conducts extensive clinical care, education and research across multiple campuses.

Its International Medical Center, founded in 1989, features one-stop services, dedicated outpatient areas, hotel-style VIP inpatient rooms and coordination with international insurers. It is designated by multiple foreign consulates in Shanghai and follows protocols aligned with international medical service standards.