# Molecular Mechanisms of Tubulin Polymerization Promoting Protein in Mitochondrial Function and Neuronal Survival

> **NIH NIH R01** · UNIVERSITY OF TEXAS HLTH SCIENCE CENTER · 2024 · $397,839

## Abstract

ABSTRACT
Parkinson’s disease (PD), Alzheimer’s disease and related dementias (AD/ADRD) are debilitating progressive
neurodegenerative diseases. These diseases have no effective treatments currently and are among the greatest
unmet challenges in healthcare today affecting millions of people globally with enormous economic and societal
burdens. These disorders are characterized by neurodegeneration among other pathologies. A highly conserved,
yet less understood family of human genes, Tubulin Polymerization Promoting Proteins (TPPP), has long been
implicated in PD and ADRD such as Lewy Body Dementia. However, the pathogenic mechanisms involving
TPPP remain unknown. We recently developed a novel fly (Drosophila) model relevant to PD by utilizing a
mutation in the single Drosophila homolog of human TPPP, named Ringer. Ringer mutants recapitulate many of
the characteristics observed in human PD patients including severe locomotor disabilities, progressive
neurodegeneration (including dopaminergic neuron loss) and mitochondrial structural damage and dysfunction.
We have made novel observations that Ringer and human TPPP are both present in mitochondrial preparations
from Drosophila and postmortem human brain tissues, respectively. Co-immunoprecipitations from fly brain
mitochondrial preparations followed by mass spectrometry-based proteomics analyses revealed that Ringer
interacts with the electron transport chain (ETC) Complex I (CI) subunits and members of the SLC25A family of
mitochondrial carrier proteins, thus highlighting a novel and unique role of Ringer in mitochondria. Our
overarching hypothesis is that Ringer interacts with CI subunits and SLC25A solute carriers to stabilize the ETC
complexes and maintain mitochondrial bioenergetics that is crucial for neuronal survival. The overall objective of
this proposal is to delineate the mechanisms of Ringer function in mitochondria and extend our studies to
postmortem human brains to determine the functional conservation of TPPP and the relevance of human TPPP
to PD and related disorders. Using enzymatic assays, respirometry, LC-MS, biochemical, behavioral,
pharmacological, cell biological and genetic methodologies, our specific aims will: (1) Determine the
consequences of Ringer loss on mitochondrial bioenergetics, (2) Identify the molecular mechanisms by which
Ringer promotes ETC function and neuronal survival, and (3) Determine the cellular and sub-cellular localization
of human TPPP and any alterations in TPPP in PD brain tissues. Our proposed studies will for the first time
uncover a novel Ringer/TPPP function in maintaining mitochondrial health which is essential to prevent neuronal
cell death. We expect that our completed studies will provide unprecedented insights into potential pathogenic
mechanisms of human TPPP in PD and related disorders, and may contribute towards uncovering therapeutic
targets in the future.

## Key facts

- **NIH application ID:** 10981129
- **Project number:** 1R01NS134867-01A1
- **Recipient organization:** UNIVERSITY OF TEXAS HLTH SCIENCE CENTER
- **Principal Investigator:** Swati Banerjee
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $397,839
- **Award type:** 1
- **Project period:** 2024-07-01 → 2029-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10981129

## Citation

> US National Institutes of Health, RePORTER application 10981129, Molecular Mechanisms of Tubulin Polymerization Promoting Protein in Mitochondrial Function and Neuronal Survival (1R01NS134867-01A1). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10981129. Licensed CC0.

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