Synaptic vesicle glycoprotein 2C (SV2C) modulates dopamine release and is disrupted in Parkinson disease

Dunn, Amy R.; Stout, Kristen A.; Ozawa, Minagi; Lohr, Kelly M.; Hoffman, Carlie; Bernstein, Alison I.; Li, Yingjie; Wang, Minzheng; Sgobio, Carmelo; Sastry, Namratha; Cai, Huaibin; Caudle, W. Michael; Miller, Gary W.

doi:10.1073/pnas.1616892114

Cited by 106 publications

(112 citation statements)

References 64 publications

(113 reference statements)

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“…It is also important to note that [ 11 C]UCB‐J has previously been found to be specific for SV2A and not for SV2B or SV2C . There is preclinical evidence of SV2C disruption in PD pathogenesis . It is possible that SV2C is selectively expressed in dopamine neurons and therefore a more sensitive marker of synaptic loss in the striatum, which would make an SV2C‐specific PET tracer potentially valuable in this regard.…”

Section: Discussionmentioning

confidence: 99%

Synaptic Changes in Parkinson Disease Assessed with in vivo Imaging

Matuskey

Tinaz

Wilcox

et al. 2020

Annals of Neurology

120

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Objective Parkinson disease is characterized by motor and nonmotor symptoms, reduced striatal dopamine signaling, and loss of dopamine neurons in the substantia nigra. It is now known that the pathological process in Parkinson disease may begin decades before the clinical diagnosis and include a variety of neuronal alterations in addition to the dopamine system. Methods This study examined the density of all synapses with synaptic vesicle glycoprotein 2A (SV2A) in Parkinson disease subjects with mild bilateral disease (n = 12) and matched normal controls (n = 12) using in vivo high‐resolution positron emission tomographic imaging as well as postmortem autoradiography in an independent sample with Parkinson disease (n = 15) and normal controls (n = 13) in the substantia nigra and putamen. Results A group‐by‐brain region interaction effect (F10, 22 = 3.52, p = 0.007) was observed in the primary brain areas with in vivo SV2A binding. Post hoc analyses revealed that the Parkinson disease group exhibited lower SV2A in the substantia nigra (−45%; p < 0.001), red nucleus (−31%; p = 0.03), and locus coeruleus (−17%; p = 0.03). Exploratory analyses also revealed lower SV2A binding in clinically relevant cortical areas. Using autoradiography, we confirmed lower SV2A in the substantia nigra (−17%; p < 0.005) and nonsignificant findings in the putamen (−4%; p = 0.06). Interpretation This work provides the first evidence of synaptic loss in brainstem nuclei involved in the pathogenesis of Parkinson disease in living patients. SV2A imaging holds promise for understanding synaptic changes central to the disease. Ann Neurol 2020;87:329–338

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Section: Discussionmentioning

confidence: 99%

Synaptic Changes in Parkinson Disease Assessed with in vivo Imaging

Matuskey

Tinaz

Wilcox

et al. 2020

Annals of Neurology

120

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“…Synaptic vesicle PG-2 SV2 occurs as three isoforms, SV2A, SV2B, and SV2C which display variable cellular distributions. These bind the neurotransmitters glutamate, GABA, dopamine, choline, and ATP and also interact with Ach and synaptotagmin (Bartholome et al 2017;Dunn et al 2017). SV2 forms a smart gel storage matrix within synaptic vesicles (Reigada et al 2003).…”

Section: Sulfation Of Ks Glycoforms On Pgs and Its Impact On Neuroregmentioning

confidence: 99%

Keratan sulfate (KS)‐proteoglycans and neuronal regulation in health and disease: the importance of KS‐glycodynamics and interactive capability with neuroregulatory ligands

Melrose

2019

Journal of Neurochemistry

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Compared to the other classes of glycosaminoglycans (GAGs), that is, chondroitin/dermatan sulfate, heparin/heparan sulfate and hyaluronan, keratan sulfate (KS), have the least known of its interactive properties. In the human body, the cornea and the brain are the two most abundant tissue sources of KS. Embryonic KS is synthesized as a linear poly‐N‐acetyllactosamine chain of d‐galactose‐GlcNAc repeat disaccharides which become progressively sulfated with development, sulfation of GlcNAc is more predominant than galactose. KS contains multi‐sulfated high‐charge density, monosulfated and non‐sulfated poly‐N‐acetyllactosamine regions and thus is a heterogeneous molecule in terms of chain length and charge distribution. A recent proteomics study on corneal KS demonstrated its interactivity with members of the Slit‐Robbo and Ephrin‐Ephrin receptor families and proteins which regulate Rho GTPase signaling and actin polymerization/depolymerization in neural development and differentiation. KS decorates a number of peripheral nervous system/CNS proteoglycan (PG) core proteins. The astrocyte KS‐PG abakan defines functional margins of the brain and is up‐regulated following trauma. The chondroitin sulfate/KS PG aggrecan forms perineuronal nets which are dynamic neuroprotective structures with anti‐oxidant properties and roles in neural differentiation, development and synaptic plasticity. Brain phosphacan a chondroitin sulfate, KS, HNK‐1 PG have roles in neural development and repair. The intracellular microtubule and synaptic vesicle KS‐PGs MAP1B and SV2 have roles in metabolite transport, storage, and export of neurotransmitters and cytoskeletal assembly. MAP1B has binding sites for tubulin and actin through which it promotes cytoskeletal development in growth cones and is highly expressed during neurite extension. The interactive capability of KS with neuroregulatory ligands indicate varied roles for KS‐PGs in development and regenerative neural processes.

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“…At the time of this GWAS finding, little was known about SV2C except that it was highly expressed in the substantia nigra and that it might be involved in dopamine release. The discovery of SV2C in GWAS prompted functional studies to decipher its role in PD and pharmacogenetic studies to test it as a candidate marker for drug response . Functional studies found that disrupted expression of SV2C is a unique pathological feature of PD; it causes reduced dopamine release in the dorsal striatum, reduced striatal dopamine content, disrupted α‐synuclein expression, abnormal motor function in rodents, and alterations in neurochemical effects of nicotine .…”

Section: Precision Medicine and Pharmacogenomicsmentioning

confidence: 99%

“…The discovery of SV2C in GWAS prompted functional studies to decipher its role in PD and pharmacogenetic studies to test it as a candidate marker for drug response . Functional studies found that disrupted expression of SV2C is a unique pathological feature of PD; it causes reduced dopamine release in the dorsal striatum, reduced striatal dopamine content, disrupted α‐synuclein expression, abnormal motor function in rodents, and alterations in neurochemical effects of nicotine . A clinical study examined SV2C and other biological variables as potential markers for l ‐dopa dose response and adverse effects .…”

Section: Precision Medicine and Pharmacogenomicsmentioning

confidence: 99%

“…54 Functional studies found that disrupted expression of SV2C is a unique pathological feature of PD; it causes reduced dopamine release in the dorsal striatum, reduced striatal dopamine content, disrupted asynuclein expression, abnormal motor function in rodents, and alterations in neurochemical effects of nicotine. 53 A clinical study examined SV2C and other biological variables as potential markers for L-dopa dose response and adverse effects. 54 The original GWAS had revealed a beneficial effect of the SV2C rs30196_C allele in interaction with smoking: the lowest PD risk was seen in individuals who had 2 copies of C and intermediate risk reduction in individuals with 1 C. A similar additive pattern was seen in the clinical study: the presence of each C allele significantly reduced L-dopa dose by 76 mg/day, suggesting that individuals who have 1 or 2 copies of the rs30196_C allele require lower doses of medication.…”

Section: Genome-wide Studies: Pharmacogenomicsmentioning

confidence: 99%

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The emerging science of precision medicine and pharmacogenomics for Parkinson's disease

Payami

2017

Movement Disorders

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Current therapies for Parkinson’s disease are problematic because they are symptomatic and have adverse effects. New drugs have failed in clinical trials due to inadequate efficacy. At the core of the problem is trying to make one drug work for all Parkinson’s disease patients, when we know this premise is wrong because (a) Parkinson’s disease is not a single disease, and (b) no two individuals have the same biological make up. Precision medicine is the goal to strive for, but we are only at the beginning stages of building the infrastructure for one of the most complex projects in the history of science, and it will be a long time before Parkinson’s disease reaps the benefits. Pharmacogenomics, a cornerstone of precision medicine, has already proven successful for many conditions, and could also propel drug discovery and improve treatment for Parkinson’s disease. To make progress in pharmacogenomics of Parkinson’s disease, we need to change course from small inconclusive candidate gene studies to large-scale rigorously planned genome-wide studies that capture the nuclear genome and the microbiome. Pharmacogenomics studies must use homogenous subtypes of Parkinson’s disease, or apply brute force of statistical power to overcome heterogeneity which will require large sample sizes achievable only via internet-based methods and electronic databases. Large-scale pharmacogenomics studies, together with biomarker discovery efforts, will yield the knowledge necessary to design clinical trials with precision, to alleviate confounding by disease heterogeneity and inter-individual variability in drug response, two of the major impediments to successful drug discovery and effective treatment.

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Synaptic vesicle glycoprotein 2C (SV2C) modulates dopamine release and is disrupted in Parkinson disease

Cited by 106 publications

References 64 publications

Synaptic Changes in Parkinson Disease Assessed with in vivo Imaging

Synaptic Changes in Parkinson Disease Assessed with in vivo Imaging

Keratan sulfate (KS)‐proteoglycans and neuronal regulation in health and disease: the importance of KS‐glycodynamics and interactive capability with neuroregulatory ligands

The emerging science of precision medicine and pharmacogenomics for Parkinson's disease

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