Decreased EAAT2 protein expression in the essential tremor cerebellar cortex.
Genetic polymorphisms in Solute carrier family 1 (glial high affinity glutamate transporter), member 2 (SLC1A2) have been linked with essential tremor. SLC1A2 encodes excitatory amino acid transporter type 2 (EAAT2), which clears glutamate from the synaptic cleft. One postulated mechanism for essential tremor is the over-excitation of glutamatergic olivo-cerebellar climbing fibers, leading to excitotoxic death of Purkinje cells. Other glutamatergic excitatory signals are transmitted to Purkinje cells via parallel fibers of cerebellar granule neurons. Therefore, the expression level of glutamate transporters could be important in essential tremor pathogenesis. Using Western blotting, we compared the expression levels of the two main glutamate transporters in the cerebellar cortex, EAAT1 and EAAT2, in postmortem tissue from 16 essential tremor cases and 13 age-matched controls. We also studied the localization of EAAT1 and EAAT2 using immunohistochemistry in 10 essential tremor cases and 12 controls. EAAT1 protein levels were similar in cases and controls (1.12 ± 0.83 vs. 1.01 ± 0.69, p =0.71) whereas EAAT2 protein levels in essential tremor cases were only 1/3 of that in controls (0.35 ± 0.23 vs. 1.00 ± 0.62, p < 0.01). Interestingly, EAAT2, but not EAAT1, was expressed in astrocytic processes surrounding the Purkinje cell axon initial segment, a region of previously observed pathological changes in essential tremor. Our main finding, a significant reduction in cerebellar cortical EAAT2 protein levels in essential tremor, suggests that Purkinje cells in essential tremor might be more vulnerable to excitotoxic damage than those of controls.
GH Sergievsky Center, College of Physicians and Surgeons, Columbia University, New York, NY, USA. ml3445@cumc.columbia.edu.
Michelle
M
Lee
Department of Neurology, College of Physicians and Surgeons, Columbia University, New York, NY, USA. melodymcheng@gmail.com.
Melody M
MM
Cheng
Department of Neurology, College of Physicians and Surgeons, Columbia University, New York, NY, USA. chiying0316@gmail.com.
Chi-Ying
CY
Lin
GH Sergievsky Center, College of Physicians and Surgeons, Columbia University, New York, NY, USA. edl2@columbia.edu.|Department of Neurology, College of Physicians and Surgeons, Columbia University, New York, NY, USA. edl2@columbia.edu.|Taub Institute for Research on Alzheimer's Disease and the Aging Brain, College of Physicians and Surgeons, Columbia University, New York, NY, USA. edl2@columbia.edu.|Department of Epidemiology, Mailman School of Public Health, Columbia University, New York, NY, USA. edl2@columbia.edu.
Elan D
ED
Louis
Department of Pathology and Cell Biology, Columbia University Medical Center and the New York Presbyterian Hospital, New York, NY, USA. plf3@columbia.edu.
Phyllis L
PL
Faust
Department of Neurology, College of Physicians and Surgeons, Columbia University, New York, NY, USA. sk3295@columbia.edu.
Sheng-Han
SH
Kuo
D000368:Aged; D000369:Aged, 80 and over; D001253:Astrocytes / Q000378:metabolism; D015153:Blotting, Western; D002525:Cerebellar Cortex / Q000378:metabolism*; D020329:Essential Tremor / Q000378:metabolism*; D027341:Excitatory Amino Acid Transporter 1 / Q000378:metabolism*; D027342:Excitatory Amino Acid Transporter 2; D005260:Female; D060005:Genotyping Techniques; D050491:Glutamate Plasma Membrane Transport Proteins / Q000378:metabolism*; D006801:Humans; D007150:Immunohistochemistry; D008297:Male
D027341:Excitatory Amino Acid Transporter 1; D027342:Excitatory Amino Acid Transporter 2; D050491:Glutamate Plasma Membrane Transport Proteins; C493397:SLC1A2 protein, human; C493394:SLC1A3 protein, human