Abnormal dopamine transporter imaging in adult-onset Niemann-Pick disease type C

Terbeek, Joanne; Latour, Philippe; Laere, Koen Van; Vandenberghe, Wim

doi:10.1016/j.parkreldis.2016.12.029

Cited by 12 publications

(5 citation statements)

References 4 publications

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“…To characterize the likely contribution of striatal component in the etiology of NPC1 disease, we analyzed the expression of effectors of DA signaling, including mDAT, D2R, and TH by Western Blot analysis of striatal samples from Npc1 nmf 164 mice at a juvenile, asymptomatic age in comparison to wt littermates. The reduction of mDAT protein levels in PN30 Npc1 nmf 164 mice is in agreement with the marked symmetrical loss of striatal DAT, especially in the putamen, observed in NPC1 patients by DAT-scan analysis (Terbeek et al, 2017; Tomic, 2018).…”

Section: Discussionsupporting

confidence: 86%

Anomalies in Dopamine Transporter Expression and Primary Cilium Distribution in the Dorsal Striatum of a Mouse Model of Niemann-Pick C1 Disease

Lucarelli

Pietro

Sala

et al. 2019

Front. Cell. Neurosci.

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The Niemann-Pick type C1 (NPC1) is a rare genetic disease characterized by the accumulation of endocytosed cholesterol and other lipids in the endosome/lysosome compartments. In the brain, the accumulation/mislocalization of unesterified cholesterol, gangliosides and sphingolipids is responsible for the appearance of neuropathological hallmarks, and progressive neurological decline in patients. The imbalance of unesterified cholesterol and other lipids, including GM2 and GM3 gangliosides, alters a number of signaling mechanisms impacting on the overall homeostasis of neurons. In particular, lipid depletion experiments have shown that lipid rafts regulate the cell surface expression of dopamine transporter (DAT) and modulate its activity. Dysregulated dopamine transporter’s function results in imbalanced dopamine levels at synapses and severely affects dopamine-induced locomotor responses and dopamine receptor-mediated synaptic signaling. Recent studies begin to correlate dopaminergic stimulation with the length and function of the primary cilium, a non-motile organelle that coordinates numerous signaling pathways. In particular, the absence of dopaminergic D2 receptor stimulation induces the elongation of dorso-striatal neuron’s primary cilia. This study has used a mouse model of the NPC1 disease to correlate cholesterol dyshomeostasis with dorso-striatal anomalies in terms of DAT expression and primary cilium (PC) length and morphology. We found that juvenile Npc1 nmf 164 mice display a reduction of dorso-striatal DAT expression, with associated alterations of PC number, length-frequency distribution, and tortuosity.

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Section: Discussionsupporting

confidence: 86%

Anomalies in Dopamine Transporter Expression and Primary Cilium Distribution in the Dorsal Striatum of a Mouse Model of Niemann-Pick C1 Disease

Lucarelli

Pietro

Sala

et al. 2019

Front. Cell. Neurosci.

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“…The involvement of deep gray nuclei has also been confirmed by 123 I-FP-CIT (ioflupane I 123 DaTSCAN) single-photon emission computed tomography (SPECT) imaging in a case of NPC, showing a marked, symmetrical loss of dopamine transporter binding, especially in the putamen 57 . This pattern has also been observed in a heterozygote patient with a “variant phenotype” in filipin staining and with high levels of plasma oxysterols 60 .…”

Section: Neuroimagingmentioning

confidence: 88%

“…Voxel-based morphometry analyses have shown a significant involvement of the hippocampus, thalamus, striatum, and cerebellum in NPC 53 – 57 . In particular, cerebellar gray matter and left thalamus volume loss were significantly correlated with Iturriaga disability scale changes and ataxia measures 53 , 58 .…”

Section: Neuroimagingmentioning

confidence: 99%

Recent neuroimaging, neurophysiological, and neuropathological advances for the understanding of NPC

Benussi

Cotelli²,

Padovani

et al. 2018

F1000Res

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Niemann–Pick disease type C (NPC) is a rare autosomal recessive lysosomal storage disorder with extensive biological, molecular, and clinical heterogeneity. Recently, numerous studies have tried to shed light on the pathophysiology of the disease, highlighting possible disease pathways common to other neurodegenerative disorders, such as Alzheimer’s disease and frontotemporal dementia, and identifying possible candidate biomarkers for disease staging and response to treatment. Miglustat, which reversibly inhibits glycosphingolipid synthesis, has been licensed in the European Union and elsewhere for the treatment of NPC in both children and adults. A number of ongoing clinical trials might hold promise for the development of new treatments for NPC. The objective of the present work is to review and evaluate recent literature data in order to highlight the latest neuroimaging, neurophysiological, and neuropathological advances for the understanding of NPC pathophysiology. Furthermore, ongoing developments in disease-modifying treatments will be briefly discussed.

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“…Previous studies in the mouse model of the Gaucher lysosomal storage disease have shown a deregulation of dopamine neurotransmission indicative of synaptic dysfunction [84]. Altered dopamine transport system imaging resulted to be pathologic in Niemann-Pick type C-case reports [85,86]. These findings together with our observations of a deregulation of proteins involved in synaptic vesicle formation and activity in the MPS IIIB mouse brain strongly suggest the involvement of synaptic dysfunction and impaired neurotransmission in the pathogenesis of the neurological disorders associated with some MPS subtypes and other lysosomal storage diseases as well.…”

Section: Deregulated Proteins Involved In Synaptic Vesicle Traffickinmentioning

confidence: 95%

Proteomic Analysis of Mucopolysaccharidosis IIIB Mouse Brain

et al. 2020

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Mucopolysaccharidosis IIIB (MPS IIIB) is an inherited metabolic disease due to deficiency of α-N-Acetylglucosaminidase (NAGLU) enzyme with subsequent storage of undegraded heparan sulfate (HS). The main clinical manifestations of the disease are profound intellectual disability and neurodegeneration. A label-free quantitative proteomic approach was applied to compare the proteome profile of brains from MPS IIIB and control mice to identify altered neuropathological pathways of MPS IIIB. Proteins were identified through a bottom up analysis and 130 were significantly under-represented and 74 over-represented in MPS IIIB mouse brains compared to wild type (WT). Multiple bioinformatic analyses allowed to identify three major clusters of the differentially abundant proteins: proteins involved in cytoskeletal regulation, synaptic vesicle trafficking, and energy metabolism. The proteome profile of NAGLU−/− mouse brain could pave the way for further studies aimed at identifying novel therapeutic targets for the MPS IIIB. Data are available via ProteomeXchange with the identifier PXD017363.

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Abnormal dopamine transporter imaging in adult-onset Niemann-Pick disease type C

Cited by 12 publications

References 4 publications

Anomalies in Dopamine Transporter Expression and Primary Cilium Distribution in the Dorsal Striatum of a Mouse Model of Niemann-Pick C1 Disease

Anomalies in Dopamine Transporter Expression and Primary Cilium Distribution in the Dorsal Striatum of a Mouse Model of Niemann-Pick C1 Disease

Recent neuroimaging, neurophysiological, and neuropathological advances for the understanding of NPC

Proteomic Analysis of Mucopolysaccharidosis IIIB Mouse Brain

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