Lysosome-Directed Strategies to Improve the Success of Neural Interfaces

Tiny electrodes placed in the brain can help doctors treat conditions like Parkinson's disease, epilepsy, and paralysis. These devices, called brain-computer interfaces (BCIs), can let a paralyzed person move a robotic arm or speak through a computer. For BCIs to function, the tissue around the newly implanted electrode must heal and form a stable connection with it. Half of the BCIs stop functioning within a year because brain tissue around the device does not heal and becomes inflamed. Electrode insertion leaves behind cellular debris such as damaged cells, blood, and fragments of the fatty coating that wraps neurons. Brain cells have built-in cleanup systems driven by organelles inside cells called lysosomes that act as recycling centers and break down this debris. However, after an electrode is implanted, lysosomes become overwhelmed and are unable to remove the cellular debris. This causes inflammation in the brain and the contact between the electrode and the brain tissue slowly fails. This project will test a new approach that uses safe gene therapy tools to boost the brain's lysosomes and help tissue heal, enabling brain implants to last for many years. The project will also support workforce development by providing internships to Pittsburgh high school students. Further, the work will enable hands-on learning for undergraduates in bioengineering and cell biology to design better brain electrodes. The work will be disseminated on a public website with demos and articles to engage the public in understanding how brain devices work. Chronic intracortical electrodes fail in nearly half of implants within one year, limiting the translation potential of BCI and neuroprosthetics. Implantation deposits cellular debris, ruptured vasculature, and myelin fragments that overwhelm the lysosomal-autophagic clearance machinery. This process produces a feed-forward cycle of stalled debris removal, persistent neuroinflammation and oligodendrocyte loss, and progressive recording degradation. This project will test the hypothesis that lysosomal capacity is the rate-limiting step in chronic implant failure and that restoring lysosomal biogenesis, and fusion competence will resolve the clearance bottleneck and improve long-term neural interface performance. The project will map the cell-type-specific evolution of lysosomal pH, autophagic flux, and lysosomal calcium dynamics in microglia, oligodendrocytes, and neurons. Further, the team will test adeno-associated virus delivery of constitutively active transcription factor EB (TFEB) to drive lysosomal biogenesis. Finally, by combining longitudinal two-photon imaging, multiplex immunohistochemistry, and chronic awake electrophysiology, the project will dissect transient receptor potential mucolipin 1 (TRPML1)-mediated lysosomal fusion through genetic knockouts in murine models. The outcomes of this work will have a significant impact in our understanding of lysosomal sufficiency as a therapeutic axis and provide design principles for next-generation implantation technology that integrates engineering and gene therapy. This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria. NSF Award ID: 2552758 | Program: 01002627DB NSF RESEARCH & RELATED ACTIVIT | Principal Investigator: Kirill Kiselyov | Institution: University of Pittsburgh, PITTSBURGH, PA | Award Amount: $550,000 View on NSF Award Search: https://www.nsf.gov/awardsearch/show-award/?AWD_ID=2552758 View on Research.gov: https://www.research.gov/awardapi-service/v1/awards/2552758.html