PMID- 9539131
OWN - NLM
STAT- MEDLINE
DCOM- 19980423
LR  - 20220409
IS  - 0896-6273 (Print)
IS  - 0896-6273 (Linking)
VI  - 20
IP  - 3
DP  - 1998 Mar
TI  - Aberrant RNA processing in a neurodegenerative disease: the cause for absent 
      EAAT2, a glutamate transporter, in amyotrophic lateral sclerosis.
PG  - 589-602
AB  - Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease that is 
      characterized by selective upper and lower motor neuron degeneration, the 
      pathogenesis of which is unknown. About 60%-70% of sporadic ALS patients have a 
      30%-95% loss of the astroglial glutamate transporter EAAT2 (excitatory amino acid 
      transporter 2) protein in motor cortex and spinal cord. Loss of EAAT2 leads to 
      increased extracellular glutamate and excitotoxic neuronal degeneration. Multiple 
      abnormal EAAT2 mRNAs, including intron-retention and exon-skipping, have now been 
      identified from the affected areas of ALS patients. The aberrant mRNAs were 
      highly abundant and were found only in neuropathologically affected areas of ALS 
      patients but not in other brain regions. They were found in 65% of sporadic ALS 
      patients but were not found in nonneurologic disease or other disease controls. 
      They were also detectable in the cerebrospinal fluid (CSF) of living ALS 
      patients, early in the disease. In vitro expression studies suggest that proteins 
      translated from these aberrant mRNAs may undergo rapid degradation and/ or 
      produce a dominant negative effect on normal EAAT2 resulting in loss of protein 
      and activity. These findings suggest that the loss of EAAT2 in ALS is due to 
      aberrant mRNA and that these aberrant mRNAs could result from RNA processing 
      errors. Aberrant RNA processing could be important in the pathophysiology of 
      neurodegenerative disease and in excitotoxicity. The presence of these mRNA 
      species in ALS CSF may have diagnostic utility.
FAU - Lin, C L
AU  - Lin CL
AD  - Johns Hopkins University, Department of Neurology, Baltimore, Maryland 21287, 
      USA.
FAU - Bristol, L A
AU  - Bristol LA
FAU - Jin, L
AU  - Jin L
FAU - Dykes-Hoberg, M
AU  - Dykes-Hoberg M
FAU - Crawford, T
AU  - Crawford T
FAU - Clawson, L
AU  - Clawson L
FAU - Rothstein, J D
AU  - Rothstein JD
LA  - eng
GR  - AG12992/AG/NIA NIH HHS/United States
GR  - NS 33958/NS/NINDS NIH HHS/United States
GR  - NS 36465/NS/NINDS NIH HHS/United States
GR  - etc.
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PT  - Research Support, U.S. Gov't, P.H.S.
PL  - United States
TA  - Neuron
JT  - Neuron
JID - 8809320
RN  - 0 (Excitatory Amino Acid Transporter 2)
RN  - 0 (RNA Precursors)
RN  - 0 (RNA, Messenger)
RN  - 0 (Receptors, Neurotransmitter)
RN  - 3KX376GY7L (Glutamic Acid)
SB  - IM
MH  - Amyotrophic Lateral Sclerosis/*genetics
MH  - Animals
MH  - Base Sequence
MH  - COS Cells/physiology
MH  - Central Nervous System/chemistry/physiology
MH  - Cloning, Molecular
MH  - Down-Regulation/genetics
MH  - Excitatory Amino Acid Transporter 2
MH  - Exons/genetics
MH  - Glutamic Acid/*metabolism
MH  - Humans
MH  - Introns/genetics
MH  - Molecular Sequence Data
MH  - Protein Biosynthesis
MH  - RNA Precursors/genetics
MH  - *RNA Processing, Post-Transcriptional
MH  - RNA, Messenger/cerebrospinal fluid/genetics
MH  - Receptors, Neurotransmitter/*genetics/metabolism
EDAT- 1998/04/16 00:00
MHDA- 1998/04/16 00:01
CRDT- 1998/04/16 00:00
PHST- 1998/04/16 00:00 [pubmed]
PHST- 1998/04/16 00:01 [medline]
PHST- 1998/04/16 00:00 [entrez]
AID - S0896-6273(00)80997-6 [pii]
AID - 10.1016/s0896-6273(00)80997-6 [doi]
PST - ppublish
SO  - Neuron. 1998 Mar;20(3):589-602. doi: 10.1016/s0896-6273(00)80997-6.