Neurogranin binds α-synuclein in the human superior temporal cortex and interaction is decreased in Parkinson’s disease

Abstract

Neurogranin is a calmodulin binding protein that has been implicated in learning and memory, long-term potentiation and synaptic plasticity. Neurons expressing neurogranin in the cortex degenerate in late stages of Parkinson’s disease with widespread α-synuclein pathology. While analyzing neurogranin gene expression levels through rtPCR in brains of mouse models overexpressing human α-synuclein, we found levels were elevated 2.5 times when compared to nontransgenic animals. Immunohistochemistry in the cortex revealed colocalization between α-synuclein and neurogranin in mouse transgenics when compared to control mice. Coimmunoprecipitation studies in the superior temporal cortex in humans confirmed interaction between α-synuclein and neurogranin, and decreased interaction between α-synuclein and neurogranin was noticed in patients diagnosed with Parkinson’s disease when compared to normal control brains. Additionally, phosphorylated neurogranin levels were also decreased in the human superior temporal cortex in patients diagnosed with Parkinson’s disease and patients diagnosed with dementia with Lewy bodies. Here, we show for the first time that neurogranin binds to α-synuclein in the human cortex, and this interaction decreases in Parkinson’s disease along with the phosphorylation of neurogranin, a molecular process thought to be involved in learning and memory.

Cerebrospinal Fluid Levels of Neurogranin in Parkinsonian Disorders

“…The present study finds strong correlations between α‐syn and Ng. This may be in line with the physical interaction between α‐syn and Ng observed in a small neuropathological study on PD and DLB patients . The investigators suggested that α‐syn interaction with Ng is important for synaptic function and decreased during onset of PDD .…”

“…This may be in line with the physical interaction between α-syn and Ng observed in a small neuropathological study on PD and DLB patients. 18 The investigators suggested that α-syn interaction with Ng is important for synaptic function and decreased during onset of PDD. 18 However, in the present study, Ng did not predict conversion to dementia in PD, nor were levels of Ng decreased in PDD compared with PD.…”

“…18 The investigators suggested that α-syn interaction with Ng is important for synaptic function and decreased during onset of PDD. 18 However, in the present study, Ng did not predict conversion to dementia in PD, nor were levels of Ng decreased in PDD compared with PD. Furthermore, we found no associations between Ng and longitudinal change in cognitive function, supporting results from one study which found no correlation between Ng and rate of change in Mini-Mental State Examination (MMSE) in PD.…”

Neurogranin as a Cerebrospinal Fluid Biomarker for Synaptic Loss in Symptomatic Alzheimer Disease

“…Additional cross-sectional studies are needed to clarify whether NGRN is specific for AD, or whether it also reflects synaptic changes in other neurodegenerative diseases. 25 …”

Disruption of Inferior Longitudinal Fasciculus Microstructure in Parkinson's Disease: A Systematic Review of Diffusion Tensor Imaging Studies

“…Importantly, various studies have shown disruptions in the occipital and temporal regions in association with motor and non-motor symptoms. For example, immunoprecipitation studies have confirmed reduced neurogranin levels, in addition to the decreased interaction between α-synuclein and neurogranin in the temporal cortex in patients suffering from PD ( 11 ). Likewise, patients with PD have shown significant differences in the gray matter (GM) volume ( 12 ), and in WM underlying the temporal, and occipital cortex as compared with normal controls ( 13 , 14 ).…”