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2016-3-14

Major points of this study

Necdin strongly stabilizes peroxisome proliferator-activated receptor coactivator-1α (PGC-1α) by inhibiting its ubiquitin-dependent degradation. Forced expression of necdin enhances mitochondrial function in neuronal cells to prevent mitochondrial respiratory chain inhibitor-induced degeneration. The overexpression of necdin in the substantia nigra in vivo of adult mice protects dopaminergic neurons against degeneration in experimental Parkinson's disease. This data reveals that necdin promotes mitochondrial biogenesis through stabilization of endogenous PGC-1α to exert neuroprotection against neurodegenerative diseases including Parkinson's disease.

Summary

PGC-1α is a master regulator of mitochondrial biogenesis and function. The peroxisome proliferator-activated receptor coactivator-1 (PGC-1) family, which consists of PGC-1α, PGC-1b and PRC, plays a central role in governing a transcriptional regulatory network for mitochondrial biogenesis and respiratory function. Here we demonstrated that necdin binds and stabilizes PGC-1α, resulting in enhancement of mitochondrial biogenesis via PGC-1α in mammalian neurons.

Necdin is a MAGE (melanoma antigen) family protein originally isolated from neurally differentiated embryonal carcinoma cells. Necdin is expressed in virtually all neurons throughout the nervous system. The necdin gene (Ndn) is expressed only from the paternal allele via genomic imprinting, a mammal-specific epigenetic regulation of gene expression. Necdin interacts with the major transcription factors E2F1 and p53 to suppress cell proliferation and apoptosis and facilitates Sirt1-mediated deacetylation of the transcription factors p53 and FoxO1 in neurons. These findings suggest that necdin interacts with major nuclear proteins to modulate the transcriptional regulation networks in mammalian neurons.

We here report that necdin facilitates neuronal mitochondrial biogenesis via PGC-1α stabilization by suppressing its proteolytic degradation in the ubiquitin-proteasomal system. Necdin forms a stable complex with PGC-1α in the nucleus of cortical neurons to maintain high mitochondrial activities. Necdin prevents oligomycin-induced neurodegeneration. Furthermore, we demonstrate that necdin prevents neurodegeneration in experimental PD models. Necdin improves mitochondrial function to reduce MPP+-induced damage of SH-SY5Y cells in vitro. Exacerbation of MPTP-induced DA neurodegeneration in Ndn-knockout mice This suggests that endogenous necdin in substantia nigra (SN) dopaminergic neurons is neuroprotective against MPTP toxicity.

Next, we investigate whether necdin overexpression exerts protective effects on dopaminergic neurons in vivo. We used adeno-associated virus (AAV)-mediated gene delivery into the SN of MPTP-based PD model mice. AAV-NDN infection significantly increases the necdin levels in the SN. AAV-mediated necdin overexpression increases the PGC-1a levels by 32% and 43% in the ipsilateral SN (compared with the contralateral SN levels) of untreated and MPTP-treated mice, respectively. Importantly, necdin almost completely abrogates MPTP-induced loss of DA cells (p=0.9659, as compared to rAAV-NDN-injected side in saline group). Furthermore, AAV-NDN-infected mice exhibited higher behavioral performance in the pole test than AAV-GFP-infected mice, indicating that necdin improves motor coordination of MPTP-treated mice. These results suggest that AAV-mediated necdin overexpression suppresses MPTP-induced degeneration of SN neurons in vivo by promoting PGC-1α-mediated mitochondrial biogenesis.

These results highlight the importance of necdin in the survival of neuronal cells, encouraging further exploration of necdin-associated pathway(s) for potential treatment of neurodegenerative diseases.

20160314-1

Necdin promotes neuronal mitochondrial biogenesis through stabilization of endogenous PGC-1α mediated by suppressing its proteolytic degradation in the ubiquitin-proteasomal system

To learn more about this research, please view the full research report entitled "Promotion of mitochondrial biogenesis by necdin protects neurons against mitochondrial insults" at this page of the Nature Communications website.

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