From October 28 to 31, 2025, the SMART Symposium on Conquering the Challenges of ALS and Related Neuromuscular Diseases was successfully held in Guangming District, Shenzhen. The symposium was co-organized by Professor Xiao-Jiang Li (Jinan University), Professor Aaron Gitler (Researcher, Shenzhen Bay Laboratory & Professor, Stanford University), and Professor Shuying Sun (Johns Hopkins University).

Neuromuscular diseases, such as amyotrophic lateral sclerosis (ALS), present a global challenge to both human health and the medical community. Every year, millions of people are affected by these conditions, yet effective treatment options remain limited. Through interdisciplinary cooperation, significant progress has been made in areas such as antisense oligonucleotides, with related therapies already approved for clinical application. The symposium brought together academic, clinical, and industrial experts in ALS and related neuromuscular diseases, fostering interdisciplinary dialogues for innovative therapeutic strategies to address these conditions.

The symposium featured a special session titled "Fighting ALS", opened by Dan Doctoroff (Former Deputy Mayor of New York City & Founder of the U.S. Target ALS Foundation) and Lei Cai (a prominent Chinese advocate and fighter against ALS). Together, they sent a powerful message of resilience to the global ALS community. Building on this opening, the symposium gathered over thirty leading scholars and pioneering researchers in the field. Keynote speakers included Professor Jeffrey Rothstein (Johns Hopkins University), Professor Don Cleveland (University of California, San Diego), and Academician Junying Yuan (Shanghai Institute of Organic Chemistry). Over three days, participants engaged in in-depth discussions spanning the entire innovation chain from disease pathogenesis to clinical translation. Motivated by scientific advancement and a shared commitment to safeguarding human health, the global fight against ALS united here, taking a firm step toward the common goal.

Focus on core pathogenesis, elucidate disease etiology 

In the session on disease pathogenesis and cellular biology, experts provided in-depth analyses from multiple perspectives. In the keynote presentations, Professor Jeffrey Rothstein (Johns Hopkins University) systematically summarized previous research on the regulation of TDP-43 nucleocytoplasmic transport. He highlighted that, beyond the nuclear pore complex, novel pathways such as mitochondrial genes can also regulate abnormal nucleocytoplasmic transport of TDP-43, offering new therapeutic targets for neurodegenerative diseases such as ALS. Professor Don Cleveland (University of California, San Diego) emphasized that aberrant phase separation of TDP-43 and decreased proteasome activity are key mechanisms driving its cytoplasmic aggregation. He further proposed a strategy to maintain its normal function through novel nuclear localization signal sequence. Academician Junying Yuan (Shanghai Institute of Organic Chemistry) described the pathological activation of apoptosis-associated kinases in neurodegenerative diseases and highlighted small-molecule inhibitors as a promising therapeutic strategy. Together, three keynote speakers elucidated critical pathogenesis of neurodegenerative diseases through distinct molecular pathways and indicated potential therapeutic directions. 

Starting from the neurobiology of ALS, Professor Magdalini Polymenidou (University of Zurich) systematically explained the key role of TDP-43 monomerization and loss of RNA-binding capacity in driving its aberrant aggregation. Professor Sandrine Da Cruz (VIB-KU Leuven) revealed that dysregulated local protein synthesis in axons, caused by aberrant FUS and TDP-43, is closely related to early neuromuscular degeneration in ALS. Professor Chunghun Lim (Korea Advanced Institute of Science and Technology) shared key mechanisms underlying lipid metabolism dysregulation in C9-ALS. Together, these findings illustrate that TDP-43 pathology involves a complex regulatory network spanning multiple levels, from the intrinsic properties of the protein itself to axonal function and cellular metabolism. 

Novel technologies and methodologies are equally crucial for elucidating disease pathogenesis. Linhao Ruan (Researcher, Huazhong University of Science and Technology) presented a study that employed a novel system to screen for key regulators of nucleocytoplasmic transport in neurons. Ruilin Tian (Assistant Professor, Southern University of Science and Technology) systematically elucidated modifiers and mechanisms in neurodegenerative diseases by developing an in vitro and in vivo screening platform, aiming to identify novel therapeutic targets. Professor Yi Lin (Tsinghua University) presented the key roles of dynamic phase separation in cellular activities and neurological diseases through investigating its molecular mechanisms and biological functions. Yun Ge (Junior Principal Investigator, Shenzhen Bay Laboratory) illustrated how targeted manipulation of protein glycosylation regulates phase separation, thereby influencing protein functions and cellular adaptability. 

The discussion was then extended to upstream regulatory processes involving RNA metabolism and stress granules. Professor Shuying Sun (Johns Hopkins University) explained strategies to modulate the processing of repetitive RNA sequences, identify genetic modifiers, and clarify their effects on RNA metabolism. Professor Christine Vande Velde (University of Montreal) reviewed the controversial roles of stress granules and presented new findings suggesting their potential neuroprotective functions. Professor Ge Bai (Zhejiang University) shared recent research indicating that specific amino acids in the diet may exacerbate ALS progression, offering valuable insights into dietary impacts. A Junior Principal Investigator from Shenzhen Bay Laboratory explained that by targeting key genes (particularly those encoding non-RNA-binding proteins) that regulate stress granule assembly, it is possible to mitigate ALS-associated neurodegeneration without completely disrupting their physiological functions. 

Collectively, these findings indicate that neurodegenerative diseases are driven by a complex molecular network, underscoring the need for systematic approaches in developing future therapeutic strategies. 

The second day of the symposium was opened with a special presentation by Manish Raisinghani (CEO of the U.S. Target ALS Foundation). He illustrated how creating a unique collaborative ecosystem has accelerated ALS research, leading to multiple clinical trials and drug development programs. Translating research findings from the laboratory to clinical practice has become a shared consensus and an essential path forward for the entire field. 

Innovate model systems, empower disease research

In the field of disease modeling and cutting-edge technologies, several experts presented innovative breakthroughs. Professor Fen-Biao Gao (UMass Chan Medical School) gained novel insights into both familial and sporadic ALS using Drosophila and iPSC models. Professor Justin Ichida (University of Southern California) employed rare genetic variants and CRISPR technology to identify new therapeutic targets. Professor Ralf Jauch (The University of Hong Kong) presented a direct somatic cell reprogramming approach to establish models of age-related neurodegenerative diseases. Professor Xiao-Jiang Li (Jinan University) shared the innovative development of a mouse model that simulates TDP-43 pathology by utilizing a primate-specific enzyme cleavage system. Professor Andrew LEE (Peking University Shenzhen Graduate School & Shenzhen Bay Laboratory) proposed a novel non-viral gene therapy using extracellular vesicles, thereby overcoming the clinical limitations associated with traditional AAV vector. 

Collectively, these findings demonstrate the innovative advances in disease modeling and cutting-edge technologies. From Drosophila and iPSC models to novel gene-edited mouse models, and from somatic cell reprogramming to non-viral delivery system, diverse technological platforms are providing increasingly powerful tools to elucidate disease pathogenesis and develop therapeutic strategies. 

Explore therapeutic strategies, advance clinical breakthroughs

Another highlight of the symposium was the diverse exploration of therapeutic strategies and clinical translation. Professor Bai Lu (Tsinghua University) presented recent advances in agonistic antibodies and small-molecule inhibitors for neuroprotection and synaptic repair. Professor Aaron Gitler (Stanford University) systematically outlined the latest discoveries of therapeutic targets for ALS. Professor Neil Shneider (Columbia University) discussed gene silencing therapies for rare genetic forms such as those involving FUS. Professor Yichang Jia (Tsinghua University) shared a complete path from disease modeling to gene therapy. Professor Gong Chen (Jinan University) highlighted the therapeutic potential of in vivo neural regeneration. Professor Yi Eve Sun (Shenzhen Institutes of Advanced Technology) presented recent progress in autologous cell reprogramming therapy. Professor Dongsheng Fan (Peking University Third Hospital) reported on clinical explorations of transcranial magnetic stimulation for ALS treatment. Professor Xiaorong Zhang (Chinese Academy of Medical Sciences) shared preclinical research progress on mitochondrial complex deficiencies in sporadic ALS. 

The discussion in this session underscored the central role of clinical strategies in ALS research. From gene therapy and cell regeneration to neuromodulation, diverse therapeutic strategies are accelerating the translation of basic target discoveries into clinical practice, offering renewed hope for overcoming intractable diseases such as ALS. 

Broaden the boundaries, inspire the new generation

On the final morning of the symposium, the session on “related neuromuscular diseases” broadened the discussion to encompass a wider scope of brain science. Professor Keqiang Ye (Shenzhen Institutes of Advanced Technology) revealed the shared pathology of NMNAT-1 and TDP-43 in Alzheimer's disease and its therapeutic significance. Professor Siqi Hong (Children's Hospital of Chongqing Medical University) provided an in-depth analysis of the current diagnostic and therapeutic landscape, as well as challenges, in pediatric neuromuscular disorders. Yelin Chen (Researcher, Shanghai Institute of Organic Chemistry) innovatively proposed a novel therapeutic strategy for Alzheimer's disease utilizing the C-terminal domain of ApoE. 

The symposium included a dedicated session of short presentations by young scholars. Young scientists from institutions including The University of Hong Kong, Southern University of Science and Technology, Sun Yat-sen University, Shenzhen Bay Laboratory, and Ractigen Therapeutics presented their cutting-edge work in disease pathogenesis, drug delivery, and technological innovation. A poster session further fostered active discussion and exchange. To encourage the development of the next generation of researchers, the symposium concluded by presenting three Best Poster Awards. 

The symposium not only provided a comprehensive overview of the latest advances and future directions in ALS and related neuromuscular disease research, but also successfully established a high-level international platform for exchange. The symposium facilitated multiple collaborative initiatives among research teams, paving the way for joint efforts to address the therapeutic challenges of ALS. The symposium was widely praised by the attending experts for its exceptional depth of discussion. Participants acknowledged that the path to conquering such complex diseases remains long, however, sustained global collaboration and innovation positions the scientific community to deliver meaningful therapeutic advances for patients worldwide.