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TDP-43 localizes predominantly in the nucleus, arranging itself into dynamic condensates through liquid\u2013liquid phase separation (LLPS). Mutations and post-translational modifications can alter the condensation properties of TDP-43, contributing to the transition of liquid-like biomolecular condensates into solid-like aggregates. However, to date it has been a challenge to study the dynamics of this process in vivo. We demonstrate through live imaging that human TDP-43 undergoes nuclear condensation in spinal motor neurons in a living animal. RNA-binding deficiencies as well as post-translational modifications can lead to aberrant condensation and altered TDP-43 compartmentalization. Single-molecule tracking revealed an altered mobility profile for RNA-binding deficient TDP-43. Overall, these results provide a critically needed in vivo characterization of TDP-43 condensation, demonstrate phase separation as an important regulatory mechanism of TDP-43 accessibility, and identify a molecular mechanism of how functional TDP-43 can be regulated.<\/jats:p>","DOI":"10.1093\/nar\/gkae112","type":"journal-article","created":{"date-parts":[[2024,2,21]],"date-time":"2024-02-21T16:10:42Z","timestamp":1708531842000},"page":"5301-5319","source":"Crossref","is-referenced-by-count":31,"title":["RNA-binding properties orchestrate TDP-43 homeostasis through condensate formation <i>in vivo<\/i>"],"prefix":"10.1093","volume":"52","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-7810-7543","authenticated-orcid":false,"given":"Natalie M","family":"Scherer","sequence":"first","affiliation":[{"name":"Faculty of Medicine, Health & Human Sciences, Macquarie Medical School, MND Research Centre, Macquarie University , Sydney , NSW\u00a0 2109 , 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