PMID- 28450545
OWN - NLM
STAT- MEDLINE
DCOM- 20170626
LR  - 20200306
IS  - 1529-2401 (Electronic)
IS  - 0270-6474 (Print)
IS  - 0270-6474 (Linking)
VI  - 37
IP  - 21
DP  - 2017 May 24
TI  - Decreased Motor Neuron Support by SMA Astrocytes due to Diminished MCP1 
      Secretion.
PG  - 5309-5318
LID - 10.1523/JNEUROSCI.3472-16.2017 [doi]
AB  - Spinal muscular atrophy (SMA) is an autosomal-recessive disorder characterized by 
      severe, often fatal muscle weakness due to loss of motor neurons. SMA patients 
      have deletions and other mutations of the survival of motor neuron 1 (SMN1) gene, 
      resulting in decreased SMN protein. Astrocytes are the primary support cells of 
      the CNS and are responsible for glutamate clearance, metabolic support, response 
      to injury, and regulation of signal transmission. Astrocytes have been implicated 
      in SMA as in in other neurodegenerative disorders. Astrocyte-specific rescue of 
      SMN protein levels has been shown to mitigate disease manifestations in mice. 
      However, the mechanism by which SMN deficiency in astrocytes may contribute to 
      SMA is unclear and what aspect of astrocyte activity is lacking is unknown. 
      Therefore, it is worthwhile to identify defects in SMN-deficient astrocytes that 
      compromise normal function. We show here that SMA astrocyte cultures derived from 
      mouse spinal cord of both sexes are deficient in supporting both WT and 
      SMN-deficient motor neurons derived from male, female, and mixed-sex sources and 
      that this deficiency may be mitigated with secreted factors. In particular, 
      SMN-deficient astrocytes have decreased levels of monocyte chemoactive protein 1 
      (MCP1) secretion compared with controls and MCP1 restoration stimulates outgrowth 
      of neurites from cultured motor neurons. Correction of MCP1 deficiency may thus 
      be a new therapeutic approach to SMA.SIGNIFICANCE STATEMENT Spinal muscular 
      atrophy (SMA) is caused by the loss of motor neurons, but astrocyte dysfunction 
      also contributes to the disease in mouse models. Monocyte chemoactive protein 1 
      (MCP1) has been shown to be neuroprotective and is released by astrocytes. Here, 
      we report that MCP1 levels are decreased in SMA mice and that replacement of 
      deficient MCP1 increases differentiation and neurite length of WT and 
      SMN-deficient motor-neuron-like cells in cell culture. This study reveals a novel 
      aspect of astrocyte dysfunction in SMA and indicates a possible approach for 
      improving motor neuron growth and survival in this disease.
CI  - Copyright (c) 2017 the authors 0270-6474/17/375309-10$15.00/0.
FAU - Martin, Jasmin E
AU  - Martin JE
AD  - Neurogenetics Branch, National Institute of Neurological Disorders and Stroke, 
      and.
FAU - Nguyen, TrangKimberly T
AU  - Nguyen TT
AUID- ORCID: 0000-0003-0928-2019
AD  - Neurogenetics Branch, National Institute of Neurological Disorders and Stroke, 
      and.
FAU - Grunseich, Christopher
AU  - Grunseich C
AD  - Neurogenetics Branch, National Institute of Neurological Disorders and Stroke, 
      and.
FAU - Nofziger, Jonathan H
AU  - Nofziger JH
AD  - Neurogenetics Branch, National Institute of Neurological Disorders and Stroke, 
      and.
FAU - Lee, Philip R
AU  - Lee PR
AD  - Section on Nervous System Development and Plasticity, Eunice Kennedy Shriver 
      National Institutes of Child Health and Human Development, National Institutes of 
      Health, Bethesda, Maryland 20892.
FAU - Fields, Douglas
AU  - Fields D
AD  - Section on Nervous System Development and Plasticity, Eunice Kennedy Shriver 
      National Institutes of Child Health and Human Development, National Institutes of 
      Health, Bethesda, Maryland 20892.
FAU - Fischbeck, Kenneth H
AU  - Fischbeck KH
AD  - Neurogenetics Branch, National Institute of Neurological Disorders and Stroke, 
      and.
FAU - Foran, Emily
AU  - Foran E
AD  - Neurogenetics Branch, National Institute of Neurological Disorders and Stroke, 
      and Emily.Carifi@nih.gov.
LA  - eng
PT  - Journal Article
PT  - Research Support, N.I.H., Intramural
DEP - 20170427
PL  - United States
TA  - J Neurosci
JT  - The Journal of neuroscience : the official journal of the Society for 
      Neuroscience
JID - 8102140
RN  - 0 (Ccl2 protein, mouse)
RN  - 0 (Chemokine CCL2)
RN  - 0 (Smn1 protein, mouse)
RN  - 0 (Survival of Motor Neuron 1 Protein)
SB  - IM
CIN - J Neurosci. 2017 Sep 6;37(36):8578-8580. PMID: 28878096
MH  - Animals
MH  - Astrocytes/cytology/*metabolism
MH  - Cells, Cultured
MH  - Chemokine CCL2/genetics/*metabolism
MH  - Female
MH  - Humans
MH  - Male
MH  - Mice
MH  - Motor Neurons/cytology/*metabolism
MH  - Muscular Atrophy, Spinal/*metabolism
MH  - Spinal Cord/cytology/metabolism
MH  - Survival of Motor Neuron 1 Protein/*genetics/metabolism
PMC - PMC5456111
OTO - NOTNLM
OT  - MCP1/CCL2
OT  - astrocytes
OT  - iPSC
OT  - motor neuron
OT  - spinal muscular atrophy
EDAT- 2017/04/30 06:00
MHDA- 2017/06/27 06:00
PMCR- 2017/11/24
CRDT- 2017/04/29 06:00
PHST- 2016/11/09 00:00 [received]
PHST- 2017/04/07 00:00 [revised]
PHST- 2017/04/19 00:00 [accepted]
PHST- 2017/04/30 06:00 [pubmed]
PHST- 2017/06/27 06:00 [medline]
PHST- 2017/04/29 06:00 [entrez]
PHST- 2017/11/24 00:00 [pmc-release]
AID - JNEUROSCI.3472-16.2017 [pii]
AID - 3472-16 [pii]
AID - 10.1523/JNEUROSCI.3472-16.2017 [doi]
PST - ppublish
SO  - J Neurosci. 2017 May 24;37(21):5309-5318. doi: 10.1523/JNEUROSCI.3472-16.2017. 
      Epub 2017 Apr 27.