{"doi":"10.1101/2025.09.05.674541","title":"A Novel Mechanism for Tauopathy in Progressive Multiple Sclerosis: Excitotoxic Misplacement of a Mitochondrial Anchor into Dendrites Driven by Tau-hyperphosphorylation","abstract":"Abstract On April 2 nd , 2025, the FDA approved a Fast Track Designation for Biogen to use Antisense Oligonucleotides (ASO) to treat tauopathy in clinical trials for Alzheimer’s Disease (AD) to meet an unmet medical need [1]. For Multiple Sclerosis (MS), there is a similar unmet medical need regarding tauopathy when MS transitions into the late, or Progressive MS that is currently incurable. AD and MS share commonality: there is comorbidity between AD and MS [2], and the recent awareness that progressive MS may be considered a secondary tauopathy [3]. This study lays the basic science foundation for a future repurposing of ASO tauopathy therapy from AD to MS. The central hypothesis is that in Progressive MS, tauopathy is not a passive bystander but an active contributor to synaptic degeneration through a novel toxic target known as DSI ( D endritic S yntaphilin I ntrusion) discovered in our laboratory. In this hypothesis, the excitotoxic N-methyl-D-aspartate receptor (NMDAR) GluN2B activates Tau hyperphosphorylation (p-Tau), leading to the mislocalization or intrusion of a mitochondrial anchor SNPH into neuronal dendrites (DSI). This causes mitochondrial damage and subsequent synapse/dendrite disintegration. In support of this hypothesis that tauopathy is a key driver of DSI, we demonstrated using primary neuronal cultures that inhibitors of p-Tau kinases and Tau-KO both completely abolish DSI. We propose that a therapy for Progressive MS is repurpose the existing FDA-approved ASO Tau knockdown therapy from AD to treat MS. Funding NIH R01 MSN233781 to SY Chiu","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2025,"id":574454,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":0,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9558,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2025-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":748959,"name":"Charlie Zhang","orcid":null,"position":1,"is_corresponding":false},{"id":884381,"name":"Dinesh Joshi","orcid":"0000-0003-1158-7890","position":2,"is_corresponding":false},{"id":350140,"name":"Jonathan E. Ploski","orcid":"0000-0001-8725-8693","position":3,"is_corresponding":false},{"id":822581,"name":"Shing Yan Chiu","orcid":"0000-0002-6532-8029","position":4,"is_corresponding":false},{"id":1114037,"name":"Deepali Mathur","orcid":null,"position":0,"is_corresponding":true}],"reference_count":31,"raw_metadata":null,"created_at":"2026-07-19T02:57:40.686992Z","pmid":null,"pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}