# BAP31 Modulates Mitochondrial Homeostasis Through PINK1/Parkin Pathway in MPTP Parkinsonism Mouse Models

## TL;DR

This study shows that BAP31 helps protect brain cells in Parkinson's disease by maintaining healthy mitochondria through a key pathway.

## Contribution

The study reveals BAP31's novel role in modulating mitochondrial homeostasis via the PINK1/Parkin pathway in Parkinsonism.

## Key findings

- BAP31 deficiency worsens motor deficits in MPTP-treated Parkinsonian mouse models.
- BAP31 regulates PINK1 transcription through Engrailed Homeobox 1, preserving mitochondrial stability.
- Loss of BAP31 leads to impaired mitophagy and increased dopaminergic neurodegeneration.

## Abstract

Parkinson’s disease (PD) is a neurodegenerative disorder characterized by age-dependent degeneration of dopaminergic neurons in the substantia nigra, a process mediated by α-synuclein aggregation, mitochondrial dysfunction, and impaired proteostasis. While BAP31—an endoplasmic reticulum protein critical for protein trafficking and degradation—has been implicated in neuronal processes, its role in PD pathogenesis remains poorly understood. To investigate the impact of BAP31 deficiency on PD progression, we generated dopamine neuron-specific BAP31 conditional knockout with DAT-Cre (cKO) mice (Slc6a3cre-BAP31fl/fl) and subjected them to MPTP-lesioned Parkinsonian models. Compared to BAP31fl/fl controls, Slc6a3cre-BAP31fl/fl mice exhibited exacerbated motor deficits following MPTP treatment, including impaired rotarod performance, reduced balance beam traversal time, and diminished climbing and voluntary motor capacity abilities. BAP31 conditional deletion showed no baseline phenotype, with deficits emerging only after MPTP. Our results indicate that these behavioral impairments correlated with neuropathological hallmarks: decreased NeuN neuronal counts, elevated GFAP astrogliosis, reduced tyrosine hydroxylase levels in the substantia nigra, and aggravated dopaminergic neurodegeneration. Mechanistically, BAP31 deficiency disrupted mitochondrial homeostasis by suppressing the PINK1–Parkin mitophagy pathway. Further analysis revealed that BAP31 regulates PINK1 transcription via the transcription factor Engrailed Homeobox 1. Collectively, our findings identify BAP31 as a neuroprotective modulator that mitigates PD-associated motor dysfunction by preserving mitochondrial stability, underscoring its therapeutic potential as a target for neurodegenerative disorders.