The mitochondrial permeability transition pore regulates neurodegeneration in Parkinson's disease mutant α‐synuclein transgenic mice

Parkinson's disease (PD) is a severe adult‐onset movement disorder caused by degeneration of dopaminergic neurons in the substantia nigra (SN) and synucleinopathy. Some forms of PD are inherited, caused by mutations in the α‐synuclein gene encoding the abundant synapse and nuclear protein α‐synuclein (α‐Syn). The mechanisms of PD leading to destruction of neurons are unresolved. Mitochondria might be sites for PD pathogenesis. Our objective was to establish direct cause‐effect relationships between PD and mitochrondiopathy. We used α‐Syn transgenic mice to test the hypothesis that the mitochondrial permeability transition pore (mPTP) is involved in PD. Mice expressing human A53T‐mutant α‐Syn driven by a Thy‐1 promoter develop a severe, age‐related, fatal PD‐like movement disorder and robust brainstem neurodegeneration involving mitochondrial pathology and cell death. Components of the multi‐protein mPTP are expressed highly in mouse SN neurons, including the voltage‐dependent anion channel, adenine nucleotide translocator, and cyclophilin D (CyPD) and are present in mitochondria marked by manganese SOD. Mutant α‐Syn associates with neuronal mitochondria appearing aggregated and swollen. Reducing the levels of CyPD by genetic ablation significantly delays disease onset and extends the lifespan of mutant α‐Syn mice. These results demonstrate that the mPTP is involved directly in PD mechanisms.