PMID- 20877346
OWN - NLM
STAT- MEDLINE
DCOM- 20110418
LR  - 20240322
IS  - 1525-0024 (Electronic)
IS  - 1525-0016 (Print)
IS  - 1525-0016 (Linking)
VI  - 18
IP  - 12
DP  - 2010 Dec
TI  - Expansive gene transfer in the rat CNS rapidly produces amyotrophic lateral 
      sclerosis relevant sequelae when TDP-43 is overexpressed.
PG  - 2064-74
LID - 10.1038/mt.2010.191 [doi]
AB  - Improved spread of transduction in the central nervous system (CNS) was achieved 
      from intravenous administration of adeno-associated virus serotype-9 (AAV9) to 
      neonatal rats. Spinal lower motor neuron transduction efficiency was estimated to 
      be 78% using the highest vector dose tested at a 12-week interval. The widespread 
      expression could aid studying diseases that affect both the spinal cord and 
      brain, such as amyotrophic lateral sclerosis (ALS). The protein most relevant to 
      neuropathology in ALS is transactive response DNA-binding protein 43 (TDP-43). 
      When expressed in rats, human wild-type TDP-43 rapidly produced symptoms germane 
      to ALS including paralysis of the hindlimbs and muscle wasting, and mortality 
      over 4 weeks that did not occur in controls. The hindlimb atrophy and weakness 
      was evidenced by assessments of rotarod, rearing, overall locomotion, muscle 
      mass, and histology. The muscle wasting suggested denervation, but there was only 
      14% loss of motor neurons in the TDP-43 rats. Tissues were negative for 
      ubiquitinated, cytoplasmic TDP-43 pathology, suggesting that altering TDP-43's 
      nuclear function was sufficient to cause the disease state. Other relevant 
      pathology in the rats included microgliosis and degenerating neuronal perikarya 
      positive for phospho-neurofilament. The expression pattern encompassed the 
      distribution of neuropathology of ALS, and could provide a rapid, relevant 
      screening assay for TDP-43 variants and other disease-related proteins.
FAU - Wang, David B
AU  - Wang DB
AD  - Department of Pharmacology, Toxicology, and Neuroscience, Louisiana State 
      University Health Sciences Center, Shreveport, Louisiana 71130, USA.
FAU - Dayton, Robert D
AU  - Dayton RD
FAU - Henning, Phillip P
AU  - Henning PP
FAU - Cain, Cooper D
AU  - Cain CD
FAU - Zhao, Li Ru
AU  - Zhao LR
FAU - Schrott, Lisa M
AU  - Schrott LM
FAU - Orchard, Elysse A
AU  - Orchard EA
FAU - Knight, David S
AU  - Knight DS
FAU - Klein, Ronald L
AU  - Klein RL
LA  - eng
GR  - R01 NS048450/NS/NINDS NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
DEP - 20100928
PL  - United States
TA  - Mol Ther
JT  - Molecular therapy : the journal of the American Society of Gene Therapy
JID - 100890581
RN  - 0 (DNA-Binding Proteins)
RN  - 0 (Recombinant Proteins)
SB  - IM
MH  - *Amyotrophic Lateral Sclerosis/etiology/physiopathology
MH  - Animals
MH  - *Central Nervous System
MH  - DNA-Binding Proteins/genetics/*metabolism
MH  - *Gene Expression
MH  - Gene Transfer Techniques
MH  - Humans
MH  - Rats
MH  - Recombinant Proteins/genetics/*metabolism
PMC - PMC2997590
EDAT- 2010/09/30 06:00
MHDA- 2011/04/19 06:00
PMCR- 2011/12/01
CRDT- 2010/09/30 06:00
PHST- 2010/09/30 06:00 [entrez]
PHST- 2010/09/30 06:00 [pubmed]
PHST- 2011/04/19 06:00 [medline]
PHST- 2011/12/01 00:00 [pmc-release]
AID - S1525-0016(16)30900-5 [pii]
AID - 10.1038/mt.2010.191 [doi]
PST - ppublish
SO  - Mol Ther. 2010 Dec;18(12):2064-74. doi: 10.1038/mt.2010.191. Epub 2010 Sep 28.