Massive transcriptome sequencing of human spinal cord tissues provides new insights into motor neuron degeneration in ALS

Anna Maria D'Erchia; Angela Gallo; Caterina Manzari; Susanna Raho; David S Horner; Matteo Chiara; Alessio Valletti; Italia Aiello; Francesca Mastropasqua; Loredana Ciaccia; Franco Locatelli; Francesco Pisani; Grazia Paola Nicchia; Maria Svelto; Graziano Pesole; Ernesto Picardi

doi:10.1038/s41598-017-10488-7

Massive transcriptome sequencing of human spinal cord tissues provides new insights into motor neuron degeneration in ALS

Sci Rep. 2017 Aug 30;7(1):10046. doi: 10.1038/s41598-017-10488-7.

Authors

Anna Maria D'Erchia^{1

2}, Angela Gallo³, Caterina Manzari², Susanna Raho³, David S Horner⁴, Matteo Chiara², Alessio Valletti², Italia Aiello², Francesca Mastropasqua¹, Loredana Ciaccia¹, Franco Locatelli³, Francesco Pisani¹, Grazia Paola Nicchia¹, Maria Svelto^{1

5

6}, Graziano Pesole^{7

8

9

10}, Ernesto Picardi^{11

12

13}

Affiliations

¹ Department of Biosciences, Biotechnology and Biopharmaceutics, University of Bari, Via Orabona 4, 70126, Bari, Italy.
² Institute of Biomembranes, Bioenergetics and Molecular Biotechnologies (IBIOM), National Research Council, Via Amendola 165/A, 70126, Bari, Italy.
³ Department of Pediatric Oncohaematology, Bambino Gesù Children's Hospital IRCCS, Piazza S. Onofrio 4, 00165, Rome, Italy.
⁴ Department of Biosciences, University of Milan, Via Celoria 26, 20133, Milan, Italy.
⁵ National Institute of Biostructures and Biosystems (INBB), Viale Medaglie D'Oro 305, 00136, Rome, Italy.
⁶ Center of Excellence in Comparative Genomics, University of Bari, Piazza Umberto I, 70121, Bari, Italy.
⁷ Department of Biosciences, Biotechnology and Biopharmaceutics, University of Bari, Via Orabona 4, 70126, Bari, Italy. graziano.pesole@uniba.it.
⁸ Institute of Biomembranes, Bioenergetics and Molecular Biotechnologies (IBIOM), National Research Council, Via Amendola 165/A, 70126, Bari, Italy. graziano.pesole@uniba.it.
⁹ National Institute of Biostructures and Biosystems (INBB), Viale Medaglie D'Oro 305, 00136, Rome, Italy. graziano.pesole@uniba.it.
¹⁰ Center of Excellence in Comparative Genomics, University of Bari, Piazza Umberto I, 70121, Bari, Italy. graziano.pesole@uniba.it.
¹¹ Department of Biosciences, Biotechnology and Biopharmaceutics, University of Bari, Via Orabona 4, 70126, Bari, Italy. ernesto.picardi@uniba.it.
¹² Institute of Biomembranes, Bioenergetics and Molecular Biotechnologies (IBIOM), National Research Council, Via Amendola 165/A, 70126, Bari, Italy. ernesto.picardi@uniba.it.
¹³ National Institute of Biostructures and Biosystems (INBB), Viale Medaglie D'Oro 305, 00136, Rome, Italy. ernesto.picardi@uniba.it.

Abstract

ALS is a devastating and debilitating human disease characterized by the progressive death of upper and lower motor neurons. Although much effort has been made to elucidate molecular determinants underlying the onset and progression of the disorder, the causes of ALS remain largely unknown. In the present work, we have deeply sequenced whole transcriptome from spinal cord ventral horns of post-mortem ALS human donors affected by the sporadic form of the disease (which comprises ~90% of the cases but which is less investigated than the inherited form of the disease). We observe 1160 deregulated genes including 18 miRNAs and show that down regulated genes are mainly of neuronal derivation while up regulated genes have glial origin and tend to be involved in neuroinflammation or cell death. Remarkably, we find strong deregulation of SNAP25 and STX1B at both mRNA and protein levels suggesting impaired synaptic function through SNAP25 reduction as a possible cause of calcium elevation and glutamate excitotoxicity. We also note aberrant alternative splicing but not disrupted RNA editing.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Amyotrophic Lateral Sclerosis / diagnosis
Amyotrophic Lateral Sclerosis / genetics*
Amyotrophic Lateral Sclerosis / metabolism
Amyotrophic Lateral Sclerosis / pathology
Autopsy
Calcium / metabolism
Cell Death
Gene Expression Regulation
Glutamic Acid / metabolism
High-Throughput Nucleotide Sequencing
Humans
Male
MicroRNAs / genetics
MicroRNAs / metabolism
Middle Aged
Motor Neurons / metabolism*
Motor Neurons / pathology
Nerve Tissue Proteins / genetics
Nerve Tissue Proteins / metabolism
Neuroglia / metabolism
Neuroglia / pathology
RNA, Messenger / genetics*
RNA, Messenger / metabolism
Signal Transduction
Spinal Cord / metabolism*
Spinal Cord / pathology
Synapses / metabolism
Synapses / pathology
Synaptosomal-Associated Protein 25 / genetics*
Synaptosomal-Associated Protein 25 / metabolism
Syntaxin 1 / genetics*
Syntaxin 1 / metabolism
Transcriptome*

Substances

MicroRNAs
Nerve Tissue Proteins
RNA, Messenger
SNAP25 protein, human
STX1B protein, human
Synaptosomal-Associated Protein 25
Syntaxin 1
Glutamic Acid
Calcium