Dataset Information

Cathepsin B p.Gly284Val Variant in Parkinson's Disease Pathogenesis.

ABSTRACT: Parkinson's disease (PD) is generally considered a sporadic disorder, but a strong genetic background is often found. The aim of this study was to identify the underlying genetic cause of PD in two affected siblings and to subsequently assess the role of mutations in Cathepsin B (CTSB) in susceptibility to PD. A typical PD family was identified and whole-exome sequencing was performed in two affected siblings. Variants of interest were validated using Sanger sequencing. CTSB p.Gly284Val was genotyped in 2077 PD patients and 615 unrelated healthy controls from the Czech Republic, Ireland, Poland, Ukraine, and the USA. The gene burden analysis was conducted for the CTSB gene in an additional 769 PD probands from Mayo Clinic Florida familial PD cohort. CTSB expression and activity in patient-derived fibroblasts and controls were evaluated by qRT-PCR, western blot, immunocytochemistry, and enzymatic assay. The CTSB p.Gly284Val candidate variant was only identified in affected family members. Functional analysis of CTSB patient-derived fibroblasts under basal conditions did not reveal overt changes in endogenous expression, subcellular localization, or enzymatic activity in the heterozygous carrier of the CTSB variant. The identification of the CTSB p.Gly284Val may support the hypothesis that the CTSB locus harbors variants with differing penetrance that can determine the disease risk.

SUBMITTER: Milanowski LM

PROVIDER: S-EPMC9266886 | biostudies-literature | 2022 Jun

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Cathepsin B p.Gly284Val Variant in Parkinson's Disease Pathogenesis.

Milanowski Lukasz M LM Hou Xu X Bredenberg Jenny M JM Fiesel Fabienne C FC Cocker Liam T LT Soto-Beasley Alexandra I AI Walton Ronald L RL Strongosky Audrey J AJ Faroqi Ayman H AH Barcikowska Maria M Boczarska-Jedynak Magdalena M Dulski Jaroslaw J Fedoryshyn Lyuda L Janik Piotr P Potulska-Chromik Anna A Karpinsky Katherine K Krygowska-Wajs Anna A Lynch Tim T Olszewska Diana A DA Opala Grzegorz G Pulyk Aleksander A Rektorova Irena I Sanotsky Yanosh Y Siuda Joanna J Widlak Mariusz M Slawek Jaroslaw J Rudzinska-Bar Monika M Uitti Ryan R Figura Monika M Szlufik Stanislaw S Rzonca-Niewczas Sylwia S Podgorska Elzbieta E McLean Pamela J PJ Koziorowski Dariusz D Ross Owen A OA Hoffman-Zacharska Dorota D Springer Wolfdieter W Wszolek Zbigniew K ZK

International journal of molecular sciences 20220625 13

Parkinson's disease (PD) is generally considered a sporadic disorder, but a strong genetic background is often found. The aim of this study was to identify the underlying genetic cause of PD in two affected siblings and to subsequently assess the role of mutations in Cathepsin B <i>(CTSB)</i> in susceptibility to PD. A typical PD family was identified and whole-exome sequencing was performed in two affected siblings. Variants of interest were validated using Sanger sequencing. CTSB p.Gly284Val w ...[more]

PMID: 35806091

Similar Datasets

Project description:Parkinson's disease (PD) is the second most important age-related neurodegenerative disorder in developed societies, after Alzheimer's disease, with a prevalence ranging from 41 per 100,000 in the fourth decade of life to over 1900 per 100,000 in people over 80 years of age. As a movement disorder, the PD phenotype is characterized by rigidity, resting tremor, and bradykinesia. Parkinson's disease -related neurodegeneration is likely to occur several decades before the onset of the motor symptoms. Potential risk factors include environmental toxins, drugs, pesticides, brain microtrauma, focal cerebrovascular damage, and genomic defects. Parkinson's disease neuropathology is characterized by a selective loss of dopaminergic neurons in the substantia nigra pars compacta, with widespread involvement of other central nervous system (CNS) structures and peripheral tissues. Pathogenic mechanisms associated with genomic, epigenetic and environmental factors lead to conformational changes and deposits of key proteins due to abnormalities in the ubiquitin-proteasome system together with dysregulation of mitochondrial function and oxidative stress. Conventional pharmacological treatments for PD are dopamine precursors (levodopa, l-DOPA, l-3,4 dihidroxifenilalanina), and other symptomatic treatments including dopamine agonists (amantadine, apomorphine, bromocriptine, cabergoline, lisuride, pergolide, pramipexole, ropinirole, rotigotine), monoamine oxidase (MAO) inhibitors (selegiline, rasagiline), and catechol-O-methyltransferase (COMT) inhibitors (entacapone, tolcapone). The chronic administration of antiparkinsonian drugs currently induces the "wearing-off phenomenon", with additional psychomotor and autonomic complications. In order to minimize these clinical complications, novel compounds have been developed. Novel drugs and bioproducts for the treatment of PD should address dopaminergic neuroprotection to reduce premature neurodegeneration in addition to enhancing dopaminergic neurotransmission. Since biochemical changes and therapeutic outcomes are highly dependent upon the genomic profiles of PD patients, personalized treatments should rely on pharmacogenetic procedures to optimize therapeutics.

Project description:A full understanding of Parkinson's Disease etiopathogenesis and of the causes of the preferential vulnerability of nigrostriatal dopaminergic neurons is still an unsolved puzzle. A multiple-hit hypothesis has been proposed, which may explain the convergence of familial, environmental and idiopathic forms of the disease. Among the various determinants of the degeneration of the neurons in Substantia Nigra pars compacta, in this review we will focus on the endotoxicity associated to dopamine dyshomeostasis. In particular, we will discuss the relevance of the reactive dopamine metabolite 3,4-dihydroxyphenylacetaldehyde (DOPAL) in the catechol-induced neurotoxicity. Indeed, the synergy between the catechol and the aldehyde moieties of DOPAL exacerbates its reactivity, resulting in modification of functional protein residues, protein aggregation, oxidative stress and cell death. Interestingly, αSynuclein, whose altered proteostasis is a recurrent element in Parkinson's Disease pathology, is considered a preferential target of DOPAL modification. DOPAL triggers αSynuclein oligomerization leading to synapse physiology impairment. Several factors can be responsible for DOPAL accumulation at the pre-synaptic terminals, i.e. dopamine leakage from synaptic vesicles, increased rate of dopamine conversion to DOPAL by upregulated monoamine oxidase and decreased DOPAL degradation by aldehyde dehydrogenases. Various studies report the decreased expression and activity of aldehyde dehydrogenases in parkinsonian brains, as well as genetic variants associated to increased risk in developing the pathology. Thus, we discuss how the deregulation of these enzymes might be considered a contributing element in the pathogenesis of Parkinson's Disease or a down-stream effect. Finally, we propose that a better understanding of the impaired dopamine metabolism in Parkinson's Disease would allow a more refined patients stratification and the design of more targeted and successful therapeutic strategies.

Dataset Information

Cathepsin B p.Gly284Val Variant in Parkinson's Disease Pathogenesis.

Publications

Cathepsin B p.Gly284Val Variant in Parkinson's Disease Pathogenesis.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets