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Neurosci Lett. 2019 Apr 23;699:59-63. doi: 10.1016/j.neulet.2019.01.042. Epub 2019 Jan 23.

Loss of nuclear REST/NRSF in aged-dopaminergic neurons in Parkinson's disease patients.

Author information

1
Department of Neurology, Graduate school of Medicine, Juntendo University, Tokyo, 113-8421, Japan.
2
Department of Neurology, Graduate school of Medicine, Juntendo University, Tokyo, 113-8421, Japan. Electronic address: s-sato@juntendo.ac.jp.
3
Department of Anatomy and Neurobiology, Graduate school of Biomedical science, Nagasaki University, Nagasaki, 852-8523, Japan.
4
Division of Neuropathology, Department of Neuroscience, The Jikei University School of Medicine, Tokyo, 105-8461, Japan.
5
Research Institute for Disease of Old Age, Juntendo University Graduate School of Medicine, Tokyo, 113-8421, Japan.

Abstract

Parkinson's disease (PD) is the second most common neurodegenerative disease. Lewy bodies and pale bodies in dopaminergic neurons in the substantia nigra are pathological hallmarks of PD. A number of neurodegenerative diseases demonstrate aggregate formation, but how these aggregates are associated with their pathogenesis remains unknown. It has been reported that repressor element-1 silencing transcription factor/neuron-restrictive silencer factor (REST/NRSF) is induced in the nuclei of aged neurons, preserves neuronal function, and protects against neurodegeneration during aging through the repression of cell death-inducing genes. The loss of REST is associated with Alzheimer's disease pathology. However, its function in dopaminergic neurons remains unknown. Here we demonstrated that REST enters the nucleus of aged dopaminergic neurons. On the other hand, REST is partially sequestrated in Lewy bodies and is mostly absent from the nucleus of neurons in brains with PD and dementia with Lewy bodies (DLB). Dopaminergic neuron-specific autophagy-deficient mice exhibit REST accumulation in aggregates. Defects in the protein quality control system induce REST mRNA expression; its gene product mainly appears in aggregates. Our results suggest that Lewy pathology disturbs normal aging processes in dopaminergic neurons by sequestering REST and the loss of REST may associate with the PD pathology.

KEYWORDS:

Dementia with Lewy bodies; Lewy body; NRSF; Parkinson’s disease; REST

PMID:
30684677
DOI:
10.1016/j.neulet.2019.01.042
[Indexed for MEDLINE]
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