The glycoprotein GPNMB is selectively elevated in the substantia nigra of Parkinson's disease patients and increases after lysosomal stress

Moloney, Elizabeth B.; Moskites, Alyssa; Ferrari, Eliza J.; Isacson, Ole; Hallett, Peter

doi:10.1016/j.nbd.2018.08.013

Cited by 98 publications

(115 citation statements)

References 71 publications

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“…It is highly relevant to note that GPNMB has a neuroprotective role for TDP43 toxicity or ALS [127, 199]. GPNMB was also described as neurodegeneration biomarker in Alzheimer’s, Parkinson’s, Gaucher’s disease and PLOSL leukodystrophy [79, 82, 124, 126, 173].…”

Section: Resultsmentioning

confidence: 99%

Atxn2-CAG100-KnockIn mouse spinal cord shows progressive TDP43 pathology associated with cholesterol biosynthesis suppression

Canet-Pons

Sen

Arsovic

et al. 2019

Preprint

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Large polyglutamine expansions in Ataxin-2 (ATXN2) cause multi-system nervous atrophy in Spinocerebellar Ataxia type 2 (SCA2). Intermediate size expansions carry a risk for selective motor neuron degeneration, known as Amyotrophic Lateral Sclerosis (ALS). Conversely, the depletion of ATXN2 prevents disease progression in ALS. Although ATXN2 interacts directly with RNA, and in ALS pathogenesis there is a crucial role of RNA toxicity, the affected functional pathways remain ill defined. Here, we examined an authentic SCA2 mouse model with Atxn2-CAG100-KnockIn for a first definition of molecular mechanisms in spinal cord pathology.Neurophysiology of lower limbs detected sensory neuropathy rather than motor denervation. Triple immunofluorescence demonstrated cytosolic ATXN2 aggregates sequestrating TDP43 and TIA1 from the nucleus. In immunoblots, this was accompanied by elevated CASP3, RIPK1 and PQBP1 abundance. RT-qPCR showed increase of Grn, Tlr7 and Rnaset2 mRNA versus Eif5a2, Dcp2, Uhmk1 and Kif5a decrease. These SCA2 findings overlap well with known ALS features. Similar to other ataxias and dystonias, decreased mRNA levels for Unc80, Tacr1, Gnal, Ano3, Kcna2, Elovl5 and Cdr1 contrasted with Gpnmb increase. Preterminal stage tissue showed strongly activated microglia containing ATXN2 aggregates, with parallel astrogliosis. Global transcriptome profiles from stages of incipient motor deficit versus preterminal age identified molecules with progressive downregulation, where a cluster of cholesterol biosynthesis enzymes including Dhcr24, Msmo1, Idi1and Hmgcs1 was prominent. Gas chromatography demonstrated a massive loss of crucial cholesterol precursor metabolites. Overall, the ATXN2 protein aggregation process affects diverse subcellular compartments, in particular stress granules, endoplasmic reticulum and receptor tyrosine kinase signaling. These findings identify new targets and potential biomarkers for neuroprotective therapies. Introduction:Within the dynamic research field into neurodegenerative disorders, the rare monogenic variant SCA2 (Spinocerebellar Ataxia type 2) gained much attention over the past decade, since its pathogenesis is intertwined with the motor neuron diseases ALS/FTLD (Amyotrophic Lateral Sclerosis / Fronto-Temporal Lobar Dementia) and with extrapyramidal syndromes such as Parkinson/PSP (Progressive Supranuclear Palsy). Particularly in the past year, it received massive interest since antisense-oligonucleotides were shown to effectively prevent the disease in mouse models, with clinical trials now being imminent. Still, there is an urgent unmet need to define the molecular events of pathogenesis and to identify biomarkers of progression in SCA2 patients, which reflect therapeutic benefits much more rapidly than clinical rating scales, brain imaging volumetry or neurophysiology measures.SCA2 was first described as separate entity in Indian patients, based on the characteristic early slowing of eye saccadic movements [222]. A molecularly homogeneous founder population of ~1,000 patients in...

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Section: Resultsmentioning

confidence: 99%

Atxn2-CAG100-KnockIn mouse spinal cord shows progressive TDP43 pathology associated with cholesterol biosynthesis suppression

Canet-Pons

Sen

Arsovic

et al. 2019

Preprint

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“…In cerebral spine fluid and brain of type 3 GD patients elevated gpNMB levels have also been observed [142]. Likewise, recently an increased level of gpNMB in the substantia nigra of PD patients was reported [143]. In mice with conditional deficiency in GCase in the white blood cell lineage Gaucher-like cells are formed.…”

Section: Lysosomal Glccer Deposits In Macrophages: Gaucher Cellsmentioning

confidence: 93%

“…These do not produce chitotriosidase or CCL18, but gpNMB does [140,144]. Inactivation of GCase with an irreversible inhibitor was found to increase gpNMB in the brain [143]. Interestingly, zebrafish and fruit flies overproduce a chitinase during GCase deficiency [130,145].…”

Section: Lysosomal Glccer Deposits In Macrophages: Gaucher Cellsmentioning

confidence: 99%

Glucocerebrosidase: Functions in and Beyond the Lysosome

Boer

Smeden

Bouwstra

et al. 2020

JCM

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Glucocerebrosidase (GCase) is a retaining β-glucosidase with acid pH optimum metabolizing the glycosphingolipid glucosylceramide (GlcCer) to ceramide and glucose. Inherited deficiency of GCase causes the lysosomal storage disorder named Gaucher disease (GD). In GCase-deficient GD patients the accumulation of GlcCer in lysosomes of tissue macrophages is prominent. Based on the above, the key function of GCase as lysosomal hydrolase is well recognized, however it has become apparent that GCase fulfills in the human body at least one other key function beyond lysosomes. Crucially, GCase generates ceramides from GlcCer molecules in the outer part of the skin, a process essential for optimal skin barrier property and survival. This review covers the functions of GCase in and beyond lysosomes and also pays attention to the increasing insight in hitherto unexpected catalytic versatility of the enzyme.

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“…More related clinical studies with larger sample sizes are urgently needed. In despite of contradictory clinical results, researchers found that GPNMB was both transcriptionally and expressively elevated in the substantia nigra areas of PD patients (Murthy et al, 2017 ; Moloney et al, 2018 ; Neal et al, 2018 ). GPNMB could involve in regulation of inflammation and immune systems (Budge et al, 2018 ), which also participated in PD pathogenesis.…”

Section: Introductionmentioning

confidence: 99%

The Association Analysis of GPNMB rs156429 With Clinical Manifestations in Chinese Population With Parkinson's Disease

Liu

et al. 2020

Front. Genet.

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Background: The mechanisms of Parkinson's disease (PD) include complicated genetic factors. The roles of newly found risk genes need to be further verified among different ethnicities. In a two-stage meta-analysis, single nucleotide polymorphism (SNP) of rs156429 in glycoprotein non-metastatic melanoma protein B ( GPNMB ) was reported to be associated with PD. So far clinical studies have focused on association between rs156429 and PD onset, however there is little evidence linking rs156429 with PD symptoms. Objective: This study aimed to investigate the possible association of GPNMB rs156429 with PD manifestations among southeastern Chinese people. Methods: Demographic variables, disease-related factors, and motor and non-motor assessments of 511 PD patients were collected. Polymerase chain reaction (PCR) and SNaPshot technique were used to detect GPNMB rs156429. The associations of rs156429 with PD rating scales and clinical manifestations were analyzed by Kruskal-Wallis test and logistic regression model separately. Results: Kruskal-Wallis test and logistic regression model failed to reveal an association between GPNMB rs156429 and scores from Montreal Cognitive Assessment (MoCA) ( p = 0.037; p = 1.000 after correction), and pain symptoms of 511 PD patients ( p = 0.008, OR = 0.59, 95% CI = 0.40–0.87, overdominant model after adjustment; p = 0.168 after correction, overdominant model after adjustment). However, further analysis based on genders showed that GPNMB rs156429 might have a trend for being associated with cognitive dysfunction (Mini-Mental State Examination (MMSE), p = 0.064 after correction; MoCA, p = 0.064 after correction) and pain symptoms ( p = 0.063 after correction, overdominant model after adjustment) in female PD patients but not male patients. Conclusions: This study revealed that GPNMB rs156429 might have a trend for being associated with cognitive dysfunction and pain symptoms of female PD patients in the southeastern Chinese population. Further studies from a larger sample size are needed to confirm these findings.

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The glycoprotein GPNMB is selectively elevated in the substantia nigra of Parkinson's disease patients and increases after lysosomal stress

Cited by 98 publications

References 71 publications

Atxn2-CAG100-KnockIn mouse spinal cord shows progressive TDP43 pathology associated with cholesterol biosynthesis suppression

Atxn2-CAG100-KnockIn mouse spinal cord shows progressive TDP43 pathology associated with cholesterol biosynthesis suppression

Glucocerebrosidase: Functions in and Beyond the Lysosome

The Association Analysis of GPNMB rs156429 With Clinical Manifestations in Chinese Population With Parkinson's Disease

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