Understanding the molecular basis of neuropsychiatric diseases and novel treatment targets
From study of patients with neuropsychiatric illnesses, including schizophrenia and bipolar disorder, we have identified biological disturbances in the periphery, which we believe reflect the CNS and can thus provide a source to pinpoint primary pathological changes that contribute to the etiology of, and susceptibility to disorders including schizophrenia, bipolar disorder and Alzheimer's disease. Through funding from the NIH (National Institute of Mental Health and National Institute of Aging), and collaborative funding from the Stanley Medical Research Institute, my program of research focuses on investigating the molecular genetic pathways leading to these peripheral abnormalities, aiming to understand susceptibility and illness progression, as well as to identify treatment targets. Some examples of how we are then translating our biological findings to test novel therapeutic approaches are described in the specific projects below.
Wu JW, Hussaini SA, Bastille IM, Rodriguez GA, Mrejeru A, Rilett K, Sanders DW, Cook C, Fu H, Boonen RA, Herman M, Nahmani E, Emrani S, Figueroa YH, Diamond MI, Clelland CL
, Wray S, Duff KE. Neuronal activity enhances tau propagation and tau pathology in vivo. Nat Neurosci
. (2016) Aug;19(8):1085-92. doi: 10.1038/nn.4328. Epub 2016 Jun 20.Clelland CL
, Drouet V, Rilett KC, Smeed JA, Nadrich RH, Rajparia A, Read LL, Clelland JD.
Evidence that COMT genotype and proline interact on negative-symptom outcomes in schizophrenia and bipolar disorder. Translational Psychiatry
(2016) 6, e891; doi:10.1038/tp.2016.157
Myeku N, Clelland CL
, Emrani S, Kukushkin NV, Yu WH, Goldberg AL, Duff KE. Tau-driven 26S proteasome impairment and cognitive dysfunction can be prevented early in disease by activating cAMP-PKA signaling. Nature Medicine
(2016) Jan;22(1):46-53. doi: 10.1038/nm.4011.
Clelland JD, Read LL, Drouet V, Kaon A, Kelly A, Duff KE, Nadrich RH, Rajparia A, Clelland CL
. Vitamin D insufficiency and schizophrenia risk: evaluation of hyperprolinemia as a mediator of association. Schizophrenia Research
(2014) Jun;156(1):15-22. doi: 10.1016/j.schres.2014.03.017. PMID: 24787057 Clelland CL
, Read LL., Panek LJ., Nadrich RH., Bancroft C., Clelland JD. Utilization of Never-Medicated Bipolar Disorder Patients in the Development and Validation of a Peripheral Biomarker Profile. PLoS One
(2013) 8(6): e69082. PMID:23826396
Liu L., Drouet V., Wu J.W., Witter M.P., Small S.A., Clelland CL
, Duff K. Trans-synaptic Spread of Tau Pathology in vivo. PloS One
(2012) 7(2): e31302. PMID: 22312444 Clelland CL
, Read LL, Baraldi AN, Bart CP, Pappas CA, Panek LJ, Nadrich RH, Clelland JD. Evidence for association of hyperprolinemia with schizophrenia and a measure of clinical outcome. Schizophrenia Research
(2011) Sep;131(1-3):139-45. PMID: 21645996 Clelland Taylor CL
and Clelland JD. miRNAs in Neurodegenerative Disorders. Advances in Neurology: Genomics, Proteomics and the Nervous System. Springer Publishers, New York. Springer, New York; 1st Edition
(2010) December 6:445-454.
Richardson MA, Read LL, Clelland JD, Reilly MA, Clelland Taylor CL
. Analysis of Plasma Biopterin Levels in Psychiatric Disorders Suggests a Common BH4 Deficit in Schizophrenia and Schizoaffective Disorder. Neurochemical Research
Richardson MA, Read LL, Clelland Taylor CL
, Reilly MA, Chao HM, Guynn RW, Suckow R, and Clelland JD. Evidence for a Tetrahydrobiopterin Deficit in Schizophrenia. Neuropsychobiology
Targeting Peripheral Elevation of Proline in Schizophrenia
. Proline is a precursor of the neurotransmitter glutamate, it is a neuromodulator at glutamatergic synapses and it has a genetic link with schizophrenia through the 22q11 PRODH gene. We recently found that over 26% of an inpatient schizophrenia sample was hyperprolinemic, meaning that these patients exhibited high levels of fasting plasma proline. Elevated CNS proline, which reflects that of the periphery, has been shown to detrimentally impact cognition in both hyperprolinemia type-I patients and patients with 22q11 deletion syndrome, and also in a hyperprolinemic mouse model of schizophrenia. Through funding from the NIMH (R01MH100219), my lab is now investigating the molecular basis of hyperprolinemia in schizophrenia and the impact of proline elevation on specific symptom domains. We are also working to identify new compounds that regulate PRODH expression and can thus target the proline elevation found in over one quarter of patients tested.Targeting a Peripheral Deficit of Tetrahydrobiopterin (BH4) in Schizophrenia, Schizoaffective Disorder, and Bipolar Disorder
. BH4 is a vital cofactor required for neurotransmitter synthesis, and our group reported a deficit of plasma biopterin (a measure of BH4) in psychiatric disorder patients. We have more recently found evidence for genetic association in psychiatric patients with a very interesting candidate gene (GCH1, which encodes the enzyme that catalyzes the rate-limiting step in BH4 biosynthesis), and my lab is investigating how dysregulation of GCH1 contributes to the BH4 deficit and also, in collaboration with researchers at the Nathan Kline Institute, whether some mood stabilizing drugs function via regulation of GCH1 and BH4 synthesis. Translating these exciting findings, and in collaboration with Dr. Jeffrey Lieberman, Chair of Psychiatry at CUMC and Director of New York State Psychiatric Institute, we are testing whether alleviation of the BH4 deficit via treatment with a synthetic BH4 supplement (6R-BH4), may give rise to an improvement of positive and negative symptoms, and neurocognitive deficits in patients with schizophrenia and schizoaffective disorder. The Role of miRNA pathway dysregulation in Human Tauopathies
. My lab is also interested in the potential role of miRNA pathway dysregulation in the etiology of neurodegenerative tauopathies. Using a murine model of tauopathy, plus tissue from human Alzheimer's disease (AD) and frontotemporal dementia (FTD), and healthy aged-matched control brain tissue, and techniques including global miRNA profiling, quantitative RT-PCR, and in situ hybridization, we are investigating the role of miRNAs in the etiology of these devastating diseases.
Honors and Awards
1993: Catherine and Hugh Stevenson PhD Funding Award
2000: Charles H Revson Fellowship in Biomedical Science.
2007: Transform K12 Mentored Career Award.
2009: Australasian Society for Bipolar Disorder Emerging Investigator Award.
2010: Gray Matters at Columbia Fellowship.