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

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.

SUBMITTER: D'Erchia AM

PROVIDER: S-EPMC5577269 | biostudies-literature | 2017 Aug

REPOSITORIES: biostudies-literature

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

D'Erchia Anna Maria AM Gallo Angela A Manzari Caterina C Raho Susanna S Horner David S DS Chiara Matteo M Valletti Alessio A Aiello Italia I Mastropasqua Francesca F Ciaccia Loredana L Locatelli Franco F Pisani Francesco F Nicchia Grazia Paola GP Svelto Maria M Pesole Graziano G Picardi Ernesto E

Scientific reports 20170830 1

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 ...[more]

PMID: 28855684

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Project description:Neurodegenerative diseases are characterized by the selective degeneration of neuronal populations in different brain regions and frequently the formation of distinct protein aggregates that often overlap between diseases. While the causes of many sporadic neurodegenerative diseases are unclear, genes associated with familial or sporadic forms of disease and the underlying cellular pathways involved tend to support common disease mechanisms. Underscoring this concept, mutations in the Vacuolar Protein Sorting 35 Orthologue (VPS35) gene have been identified to cause late-onset, autosomal dominant familial Parkinson's disease, whereas reduced VPS35 protein levels are reported in vulnerable brain regions of subjects with Alzheimer's disease, neurodegenerative tauopathies such as progressive supranuclear palsy and Pick's disease, and amyotrophic lateral sclerosis. Therefore, VPS35 is commonly implicated in many neurodegenerative diseases. VPS35 plays a critical role in the retromer complex that mediates the retrieval and recycling of transmembrane protein cargo from endosomes to the trans-Golgi network or plasma membrane. VPS35 and retromer function are highly conserved in eukaryotic cells, with the homozygous deletion of VPS35 inducing early embryonic lethality in mice that has hindered an understanding of its role in the brain. Here, we develop conditional knockout mice with the selective deletion of VPS35 in neurons to better elucidate its role in neuronal viability and its connection to neurodegenerative diseases. Surprisingly, the pan-neuronal deletion of VPS35 induces a progressive and rapid disease with motor deficits and early post-natal lethality. Underlying this neurological phenotype is the relatively selective and robust degeneration of motor neurons in the spinal cord. Neuronal loss is accompanied and preceded by the formation of p62-positive protein inclusions and robust reactive astrogliosis. Our study reveals a critical yet unappreciated role for VPS35 function in the normal maintenance and survival of motor neurons during post-natal development that has important implications for neurodegenerative diseases, particularly amyotrophic lateral sclerosis.

Dataset Information

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

Publications

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

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