Abstract
Mutations in α-synuclein gene have been linked to familial early-onset Parkinson’s disease (PD) with Lewy body pathology. A30P mutant α-synuclein is believed to suppress autophagic progression associated with PD pathogenesis. However, the mechanistic link between A30P mutation and autophagy inhibition in PD remains poorly understood. In this study, we identified that A30P mutant α-synuclein resulted in reduced autophagy flux through promoting the decrease of autophagosomal membrane-associated protein LC3 and the increase of SQSTM1/p62 protein levels in midbrain dopaminergic neuron, due to the transcriptional repressor ZKSCAN3 trafficking from the cytoplasm to the nucleus. Moreover, the results demonstrated that A30P mutant α-synuclein not only decreased the phospho-c-Jun N-terminal Kinase (p-JNK) levels in midbrain dopaminergic neuron but also interfered autophagy without influencing the activities of AMPK and mTOR. Collectively, the present study reveals a novel autophagy inhibition mechanism induced by A30P mutant α-synuclein via transcriptional activation of the ZKSCAN3 in a JNK-dependent manner.
Highlights
Parkinson’s disease (PD) is the second most common neurodegenerative disorder characterized by the progressive degeneration of dopaminergic (DA) neurons in the substantia nigra pars compacta of the midbrain as a result of the formation of intraneuronal inclusions called Lewy bodies and Lewy neurites, mainly composed of αsynuclein1–3. α-Synuclein is a 14-kDa, intrinsically disordered protein and mainly localizes in the presynaptic nerve terminals
We report that A30P mutant α-synuclein suppresses autophagy activity by decreasing the induction of Jun N-terminal Kinase (JNK)-mediated ZKSCAN3 nuclear translocation in midbrain dopaminergic neuron
To demonstrate that the increase in p62 levels after mutant A30P α-synuclein transfection was mediated by autophagy inhibition; the levels of insoluble p62 were determined by immunoblotting in midbrain dopaminergic neurons
Summary
Parkinson’s disease (PD) is the second most common neurodegenerative disorder characterized by the progressive degeneration of dopaminergic (DA) neurons in the substantia nigra pars compacta of the midbrain as a result of the formation of intraneuronal inclusions called Lewy bodies and Lewy neurites, mainly composed of αsynuclein1–3. α-Synuclein is a 14-kDa, intrinsically disordered protein and mainly localizes in the presynaptic nerve terminals. Parkinson’s disease (PD) is the second most common neurodegenerative disorder characterized by the progressive degeneration of dopaminergic (DA) neurons in the substantia nigra pars compacta of the midbrain as a result of the formation of intraneuronal inclusions called Lewy bodies and Lewy neurites, mainly composed of αsynuclein. Pathologically aggregated α-synuclein may spread from one neuron to the other throughout the brain during PD pathogenesis, widely implicated α-synuclein as a central part of the disease process[7,8]. These pathological changes could result in a cellular stress condition that interferes with intracellular clearance pathways and favor α-synuclein further aggregation.
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