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Consequently, robust biomarkers are urgently needed to monitor therapeutic efficacy and safety of potential therapeutic interventions. Neurofilament light chain has emerged as a leading candidate, serving as a sensitive pharmacodynamic biomarker of neuronal injury and treatment response in neurodegenerative disorders. This review explores the utility of neurofilament light chain across various ataxias, including polyglutamine spinocerebellar ataxias, Friedreich\u2019s ataxia, multiple system atrophy, and other genetic ataxias, such as ataxias associated with RCF1 and SPG7 genes. We synthesize evidence from recent studies that have used ultra-sensitive assays. These studies consistently demonstrate elevated neurofilament light chain levels in cerebrospinal fluid and blood, correlating with disease severity, progression and neuroimaging findings. Notably, neurofilament light chain levels rise during the presymptomatic stage in spinocerebellar ataxias, highlighting its potential for stratifying individuals for trial enrolment and tracking therapeutic effects. A treatment-induced reduction in neurofilament light chain could function as a surrogate endpoint for target engagement, analogous to its validated use in amyotrophic lateral sclerosis. Finally, we discuss the results of other studies conducted on other biomarkers, including glial fibrillary acidic protein, total tau and phosphorylated tau, which may reflect complementary aspects of neurodegeneration and glial activation. Glial fibrillary acidic protein may provide insights into astroglial reactivity and neuroinflammation. Similarly, alteration in total tau and phosphorylated tau levels may suggest dysfunction in neuronal cytoskeleton and axonal integrity. The review also focuses on target-engagement biomarkers, including polyglutamine-expanded ataxin proteins in spinocerebellar ataxias and frataxin in Friedreich\u2019s ataxia, as critical tools to complement the ataxia biomarker toolkit. The quantification of mutant ataxin proteins provides a mechanistic readout for emerging gene-silencing or protein-lowering therapies. In parallel, the measurement of frataxin levels serves as a pharmacodynamic marker in therapeutic strategies aiming to restore frataxin expression. These target-engagement biomarkers are valuable in early phases of clinical trials, which mainly aim to demonstrate the biological activity of a treatment before later-phase trials assessing clinical efficacy. Finally, we report on somatic instability in polyglutamine spinocerebellar ataxias as an emerging and highly relevant therapeutic target. CAG repeat mosaicism is gene specific and correlates with disease progression. Integrating measures of repeat instability with neurodegenerative biomarkers could provide a comprehensive monitoring approach in clinical studies. This overview underscores the potential of fluid biomarkers, particularly neurofilament light chain, in accelerating therapeutic development for hereditary ataxias.<\/jats:p>","DOI":"10.1093\/braincomms\/fcag313","type":"journal-article","created":{"date-parts":[[2026,10,1]],"date-time":"2026-10-01T11:44:44Z","timestamp":1790855084000},"source":"Crossref","is-referenced-by-count":0,"title":["The role of neurofilament light chain and other fluid biomarkers in cerebellar ataxias"],"prefix":"10.1093","volume":"8","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9569-9229","authenticated-orcid":false,"given":"Charlotte","family":"Mouraux","sequence":"first","affiliation":[{"name":"Sorbonne Universit\u00e9, Paris Brain Institute\u2014ICM, Inserm, CNRS, APHP, Piti\u00e9-Salp\u00eatri\u00e8re University Hospital , Paris 75013 ,","place":["France"]},{"name":"GIGA\u2014CRC Human Imaging\u2014Rare Movement Disorders Research Group, University of Li\u00e8ge , Li\u00e8ge 4000 ,","place":["Belgium"]},{"name":"Department of Human Genetics, University Hospital of Li\u00e8ge , Li\u00e8ge 4000 ,","place":["Belgium"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Magda M","family":"Santana","sequence":"additional","affiliation":[{"name":"Sorbonne Universit\u00e9, Paris Brain Institute\u2014ICM, Inserm, CNRS, APHP, Piti\u00e9-Salp\u00eatri\u00e8re University Hospital , Paris 75013 ,","place":["France"]},{"name":"Center for Neuroscience and Cell Biology, University of Coimbra (CNC-UC) , Coimbra 3004-504 ,","place":["Portugal"]},{"name":"Center for Innovative Biomedicine and Biotechnology (CIBB) , Coimbra 3004-504 ,","place":["Portugal"]},{"name":"Gene Therapy Center of Excellence (GeneT) , Coimbra 3004-504 ,","place":["Portugal"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Liana S","family":"Rosenthal","sequence":"additional","affiliation":[{"name":"Department of Neurology, Johns Hopkins University School of Medicine , Baltimore, MD 21287 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2208-5311","authenticated-orcid":false,"given":"Andrea","family":"Cortese","sequence":"additional","affiliation":[{"name":"Department of Neuromuscular Diseases, UCL Queen Square Institute of Neurology , London WC1N 3BG ,","place":["UK"]},{"name":"Department Medical Biotechnology and Translational Medicine, Universit\u00e0 Degli Studi Di Milano , Milan 20133 ,","place":["Italy"]},{"name":"Unit of Rare Neurological Diseases, Department of Clinical Neurosciences, Fondazione IRCCS Istituto Neurologico Carlo Besta , Milan 20133 ,","place":["Italy"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1359-9062","authenticated-orcid":false,"given":"Filippo M","family":"Santorelli","sequence":"additional","affiliation":[{"name":"Neurobiology and Molecular Medicine Unit, IRCCS Fondazione Stella Maris , Pisa 56128 ,","place":["Italy"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Puneet","family":"Opal","sequence":"additional","affiliation":[{"name":"Denning Ataxia Center, Department of Neurology, Northwestern University Feinberg School of Medicine , Chicago, IL 60611 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giulia","family":"Coarelli","sequence":"additional","affiliation":[{"name":"Sorbonne Universit\u00e9, Paris Brain Institute\u2014ICM, Inserm, CNRS, APHP, Piti\u00e9-Salp\u00eatri\u00e8re University Hospital , Paris 75013 ,","place":["France"]},{"name":"Genetics Department, DMU BioGeMH, Piti\u00e9-Salp\u00eatri\u00e8re University Hospital , Paris 75013 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