Normal Molecular Specification and Neurodegenerative Disease-Like Death of Spinal Neurons Lacking the SNARE-Associated Synaptic Protein Munc18-1.

TitleNormal Molecular Specification and Neurodegenerative Disease-Like Death of Spinal Neurons Lacking the SNARE-Associated Synaptic Protein Munc18-1.
Publication TypeJournal Article
Year of Publication2016
AuteursLaw, C, Profes, MSchaan, Lévesque, M, Kaltschmidt, JA, Verhage, M, Kania, A
JournalJ Neurosci
Volume36
Issue2
Pagination561-76
Date Published2016 Jan 13
ISSN1529-2401
KeywordsAnimals, Basic Helix-Loop-Helix Transcription Factors, Cell Death, DCC Receptor, Disks Large Homolog 4 Protein, Embryo, Mammalian, Female, Gene Expression Regulation, Developmental, Glial Cell Line-Derived Neurotrophic Factor, Guanylate Kinases, Male, Membrane Proteins, Mice, Mice, Transgenic, Motor Neurons, Munc18 Proteins, Nerve Tissue Proteins, Neurodegenerative Diseases, Oligodendrocyte Transcription Factor 2, Protein Transport, Receptor, trkB, Receptors, Cell Surface, Signal Transduction, Spinal Cord, Syntaxin 1, Tumor Suppressor Proteins
Abstract

UNLABELLED: The role of synaptic activity during early formation of neural circuits is a topic of some debate; genetic ablation of neurotransmitter release by deletion of the Munc18-1 gene provides an excellent model to answer the question of whether such activity is required for early circuit formation. Previous analysis of Munc18-1(-/-) mouse mutants documented their grossly normal nervous system, but its molecular differentiation has not been assessed. Munc18-1 deletion in mice also results in widespread neurodegeneration that remains poorly characterized. In this study, we demonstrate that the early stages of spinal motor circuit formation, including motor neuron specification, axon growth and pathfinding, and mRNA expression, are unaffected in Munc18-1(-/-) mice, demonstrating that synaptic activity is dispensable for early nervous system development. Furthermore, we show that the neurodegeneration caused by Munc18-1 loss is cell autonomous, consistent with apparently normal expression of several neurotrophic factors and normal GDNF signaling. Consistent with cell-autonomous degeneration, we demonstrate defects in the trafficking of the synaptic proteins Syntaxin1a and PSD-95 and the TrkB and DCC receptors in Munc18-1(-/-) neurons; these defects do not appear to cause ER stress, suggesting other mechanisms for degeneration. Finally, we demonstrate pathological similarities to Alzheimer's disease, such as altered Tau phosphorylation, neurofibrillary tangles, and accumulation of insoluble protein plaques. Together, our results shed new light upon the neurodegeneration observed in Munc18-1(-/-) mice and argue that this phenomenon shares parallels with neurodegenerative diseases.SIGNIFICANCE STATEMENT: In this work, we demonstrate the absence of a requirement for regulated neurotransmitter release in the assembly of early neuronal circuits by assaying transcriptional identity, axon growth and guidance, and mRNA expression in Munc18-1-null mice. Furthermore, we characterize the neurodegeneration observed in Munc18-1 mutants and demonstrate that this cell-autonomous process does not appear to be a result of defects in growth factor signaling or ER stress caused by protein trafficking defects. However, we find the presence of various pathological hallmarks of Alzheimer's disease that suggest parallels between the degeneration in these mutants and neurodegenerative conditions.

DOI10.1523/JNEUROSCI.1964-15.2016
Alternate JournalJ. Neurosci.
PubMed ID26758845
PubMed Central IDPMC4710775
Grant ListP30 CA008748 / CA / NCI NIH HHS / United States
R01 NS083998 / NS / NINDS NIH HHS / United States
/ / Canadian Institutes of Health Research / Canada