Variants in saposin D domain of prosaposin gene linked to Parkinson’s disease

There is no author summary for this article yet. Authors can add summaries to their articles on ScienceOpen to make them more accessible to a non-specialist audience.

Abstract

Recently, the genetic variability in lysosomal storage disorders has been implicated in the pathogenesis of Parkinson’s disease. Here, we found that variants in prosaposin (PSAP), a rare causative gene of various types of lysosomal storage disorders, are linked to Parkinson’s disease. Genetic mutation screening revealed three pathogenic mutations in the saposin D domain of PSAP from three families with autosomal dominant Parkinson’s disease. Whole-exome sequencing revealed no other variants in previously identified Parkinson’s disease-causing or lysosomal storage disorder-causing genes. A case-control association study found two variants in the intronic regions of the PSAP saposin D domain (rs4747203 and rs885828) in sporadic Parkinson’s disease had significantly higher allele frequencies in a combined cohort of Japan and Taiwan. We found the abnormal accumulation of autophagic vacuoles, impaired autophagic flux, altered intracellular localization of prosaposin, and an aggregation of α-synuclein in patient-derived skin fibroblasts or induced pluripotent stem cell-derived dopaminergic neurons. In mice, a Psap saposin D mutation caused progressive motor decline and dopaminergic neurodegeneration. Our data provide novel genetic evidence for the involvement of the PSAP saposin D domain in Parkinson’s disease.

Related collections

Most cited references 28

Record: found
Abstract: found
Article: not found

Activation of β-Glucocerebrosidase Reduces Pathological α-Synuclein and Restores Lysosomal Function in Parkinson's Patient Midbrain Neurons.

Joseph Mazzulli, Friederike Zunke, Taiji Tsunemi … (2016)

Parkinson's disease (PD) is characterized by the accumulation of α-synuclein (α-syn) within Lewy body inclusions in the nervous system. There are currently no disease-modifying therapies capable of reducing α-syn inclusions in PD. Recent data has indicated that loss-of-function mutations in the GBA1 gene that encodes lysosomal β-glucocerebrosidase (GCase) represent an important risk factor for PD, and can lead to α-syn accumulation. Here we use a small-molecule modulator of GCase to determine whether GCase activation within lysosomes can reduce α-syn levels and ameliorate downstream toxicity. Using induced pluripotent stem cell (iPSC)-derived human midbrain dopamine (DA) neurons from synucleinopathy patients with different PD-linked mutations, we find that a non-inhibitory small molecule modulator of GCase specifically enhanced activity within lysosomal compartments. This resulted in reduction of GCase substrates and clearance of pathological α-syn, regardless of the disease causing mutations. Importantly, the reduction of α-syn was sufficient to reverse downstream cellular pathologies induced by α-syn, including perturbations in hydrolase maturation and lysosomal dysfunction. These results indicate that enhancement of a single lysosomal hydrolase, GCase, can effectively reduce α-syn and provide therapeutic benefit in human midbrain neurons. This suggests that GCase activators may prove beneficial as treatments for PD and related synucleinopathies.

0 comments Cited 121 times – based on 0 reviews      Review now

Bookmark

Record: found
Abstract: found
Article: not found

Penetrance of Parkinson disease in glucocerebrosidase gene mutation carriers.

B Bonaïti, Hosam Elbaz, J. Pollak … (2012)

Glucocerebrosidase (GBA) gene mutations represent a strong risk factor for Parkinson disease (PD). PD penetrance in GBA mutation carriers, which represents a key issue for genetic counseling, especially for relatives of patients with Gaucher disease (GD), is unknown. Our objective was to estimate PD penetrance in a familial study of GBA mutation carriers. Probands with familial PD were recruited through the French Parkinson Disease Genetic Study Group. All GBA exons were sequenced in probands and their relatives. To estimate the age-specific cumulative PD risk (i.e., penetrance) in GBA mutation carriers, we used the proband's phenotype exclusion likelihood method and corrected for selection of familial cases by considering the status of one affected relative per family as unknown. Of 525 probands with familial PD, 24 (4.6%) were GBA mutation carriers. Of their 256 relatives, 43 (16.8%) had PD and 26 of 32 affected relatives tested for GBA mutations were mutation carriers; 213 relatives did not have PD and 31 of 71 of unaffected relatives tested for GBA mutations were mutation carriers. Under a dominant model, penetrance was estimated as 7.6%, 13.7%, 21.4%, and 29.7% at 50, 60, 70, and 80 years, respectively. There was no significant difference in penetrance at 70 years between N370S carriers, L444P carriers, and carriers of rarer mutations. The relatively high penetrance estimate in GBA carriers obtained in this study should lead to consideration of GBA as a dominant causal gene with reduced penetrance and should be taken into account for genetic counseling in relatives of patients with GD and patients with GBA-associated PD.

0 comments Cited 103 times – based on 0 reviews      Review now

Bookmark

Record: found
Abstract: found
Article: not found

ER retention and degradation as the molecular basis underlying Gaucher disease heterogeneity.

Mia Horowitz, Idit Ron (2005)

Gaucher disease (GD), an autosomal recessive disease, is characterized by accumulation of glucosylceramide mainly in cells of the reticuloendothelial system, due to mutations in the acid beta-glucocerebrosidase gene. Some of the patients suffer from neurological symptoms (type 2 and type 3 patients), whereas patients with type 1 GD do not present neurological signs. The disease is heterogeneous even among patients with the same genotype, implicating that a mutation in the glucocerebrosidase gene is required to cause GD but other factors play an important role in the manifestation of the disease. Glucocerebrosidase is a lysosomal enzyme, synthesized on endoplasmic reticulum (ER)-bound polyribosomes and translocated into the ER. Following N-linked glycosylations, it is transported to the Golgi apparatus, from where it is trafficked to the lysosomes. In this study, we tested glucocerebrosidase protein levels, N-glycans processing and intracellular localization in skin fibroblasts derived from patients with GD. Our results strongly suggest that mutant glucocerebrosidase variants present variable levels of ER retention and undergo ER-associated degradation in the proteasomes. The degree of ER retention and proteasomal degradation is one of the factors that determine GD severity.

0 comments Cited 103 times – based on 0 reviews      Review now

Bookmark

All references

Author and article information

Journal

Title: Brain

Publisher: Oxford University Press (OUP)

ISSN (Print): 0006-8950

ISSN (Electronic): 1460-2156

Publication date Created: March 23 2020

Publication date (Electronic): March 23 2020

Affiliations

[1 ]Department of Neurology, Juntendo University Graduate School of Medicine, Tokyo, Japan

[2 ]Research Institute for Diseases of Old Age, Juntendo University Graduate School of Medicine, Tokyo, Japan

[3 ]Center for Genomic and Regenerative Medicine, Juntendo University Graduate School of Medicine, Tokyo, Japan

[4 ]Department of Neurology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan

[5 ]Department of Pathophysiology and Metabolism, Kawasaki Medical School, Okayama, Japan

[6 ]Laboratory of Morphology and Image Analysis, Research Support Center, Juntendo University Graduate School of Medicine, Tokyo, Japan

[7 ]Department of Neurology, Hommachi Neurological Clinic, Nagoya, Japan

[8 ]Department of Neurology, Fujita Health University School of Medicine, Aichi, Japan

[9 ]Department of Neurology, Tokyo Metropolitan Neurological Hospital, Tokyo, Japan

[10 ]Department of Neurology, Graduate School of Medical Sciences, University of Yamanashi, Yamanashi, Japan

[11 ]Department of Neurology and Neurobiology of Aging, Kanazawa University Graduate School of Medical Science, Kanazawa, Japan

[12 ]Department of Medical Genetics, University of British Columbia, Vancouver, Canada

[13 ]Department of Neurology, University of Florida, Gainesville, USA

[14 ]Department of Cellular and Molecular Neuropathology, Juntendo University Graduate School of Medicine, Tokyo, Japan

[15 ]Department of Neurology, Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Taoyuan, Taiwan

Article

DOI: 10.1093/brain/awaa064

PubMed ID: 32201884

SO-VID: 2eda32ad-3705-4057-a8ae-697a3e05b76c

License:

https://academic.oup.com/journals/pages/open_access/funder_policies/chorus/standard_publication_model

Variants in saposin D domain of prosaposin gene linked to Parkinson’s disease

Read this article at

Abstract

Related collections

The Dynamic Brain

Most cited references 28

Activation of β-Glucocerebrosidase Reduces Pathological α-Synuclein and Restores Lysosomal Function in Parkinson's Patient Midbrain Neurons.

Penetrance of Parkinson disease in glucocerebrosidase gene mutation carriers.

ER retention and degradation as the molecular basis underlying Gaucher disease heterogeneity.

Author and article information

Journal

Affiliations

Article

History

Comments

Comment on this article

Similar content 744

Cited by 29

Most referenced authors 1,477