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Dysregulation of Reelin Protein in Autism

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Session 1: Neuropathology of Autism

S.H. Fatemi, M.D., Ph.D.
Associate Professor of Psychiatry
Adjunct Associate Professor of Neuroscience

A number of recent reports implicate Reelin, a secretory extracellular protein, in the etiology of several neurodevelopmental disorders i.e., schizophrenia (1,2), bipolar disorder (1,2), major depression (2), autism (3,4,5), and lissencephaly (6). Moreover, converging data point to Reelin as an important modulator of a neuronal signaling system that may be involved in synaptic transmission and plasticity (7). Reelin is a glycoprotein with a molecular mass of 388 kDa whose absence leads to CNS abnormalities such as inverted cortical lamination, abnormal positioning of neurons, and aberrant orientation of cell bodies and fibers in an autosomal recessive mouse mutant known as the reeler (8). These mice exhibit ataxia and a reeling gait. Reelin protein is detected early in mammalian embryogenesis and then increases in concentration up to early postnatal stages and then declines to adult levels (9). We quantified levels of Reelin and its isoforms in autistic (N=5) and normal control (N=8) cerebellar tissues matched for age, sex, and post-mortem interval using antiReelin antibodies. The results showed robust reductions of 43-44% in Reelin 410 and its isoforms in the autistic cerebella as compared to controls (p<0.04 for Reelin 180 kDa species). Measurement of $-actin in the same homogenates did not differ significantly between groups. Persico, et al (3) also showed a significant association between autism and RELN gene variants using case-control and family based designs. Overall, these results strongly suggest that Reelin deficiency may be an important contributing factor in the genesis of autism and should be further studied as a potential target for diagnosis, prevention, and treatment of this debilitating disease. (SHF acknowledges generous support by MMF, Stanley & Kunin Funds, and TARF and its associated brain banks for provision of brain samples). (1) Guidotti et al, Arch Gen Psych, 2000. (2) Fatemi, SH et al, Mol Psychiatry, 2000. (3) Persico, AM et al, J Autism Devel Dis, 2001. (4) Fatemi, SH et al, Mol Psychiatry, 2001. (5) Fatemi, SH et al, J Autism Devel Dis, 2001. (6) Hong, SE et al, Nature Gen, 2000. (7) Rodriguez et al, PNAS, 2000; (8) Falconer, DS, J Genetics, 1950; (9) Goffinett, AM, Nature, 1997.

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Last Updated Date: 11/30/2012
Last Reviewed Date: 11/30/2012
Vision National Institutes of Health Home BOND National Institues of Health Home Home Storz Lab: Section on Environmental Gene Regulation Home Machner Lab: Unit on Microbial Pathogenesis Home Division of Intramural Population Health Research Home Bonifacino Lab: Section on Intracellular Protein Trafficking Home Lilly Lab: Section on Gamete Development Home Lippincott-Schwartz Lab: Section on Organelle Biology