VPS13C-associated Parkinson's disease: Two novel cases and review of the literature

Monfrini, Edoardo; Spagnolo, Fabio; Canesi, Margherita; Seresini, Agostino; Rini, Augusto Maria; Passarella, Bruno; Percetti, Marco; Seia, Manuela; Goldwurm, Stefano; Cereda, Viviana; Comi, Giacomo Pietro; Pezzoli, Gianni; Fonzo, Alessio Di

doi:10.1016/j.parkreldis.2021.11.031

Cited by 13 publications

(9 citation statements)

References 7 publications

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“…To our knowledge, only 18 VPS13C -related PD cases have been clinically and genetically described to date, with earlier onset (37.5 ± 10.5 years of age) and faster clinical progression compared to idiopathic PD [ 152 ]. From a motor perspective, VPS13C -related PD is generally characterized by classical features such as bradykinesia, rigidity, rest tremor, freezing, and postural instability, as well as by distinct features including dystonia and, more rarely, pyramidal signs.…”

Section: Monogenic Causes Of Pd Associated With Endolysosomal and Ves...mentioning

confidence: 99%

“…Concerning non-motor features, dysautonomia, hyposmia, early cognitive decline, and visual hallucinations are presented. Dopaminergic therapy is usually effective, though MF and LID are common [ 43 , 150 , 152 , 153 , 154 , 155 , 156 , 157 ]. Neuropathological studies have shown diffuse LBD [ 43 , 150 , 152 , 153 , 154 , 155 , 156 , 157 ].…”

Section: Monogenic Causes Of Pd Associated With Endolysosomal and Ves...mentioning

confidence: 99%

“…Dopaminergic therapy is usually effective, though MF and LID are common [ 43 , 150 , 152 , 153 , 154 , 155 , 156 , 157 ]. Neuropathological studies have shown diffuse LBD [ 43 , 150 , 152 , 153 , 154 , 155 , 156 , 157 ].…”

Section: Monogenic Causes Of Pd Associated With Endolysosomal and Ves...mentioning

confidence: 99%

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Genetic Evidence for Endolysosomal Dysfunction in Parkinson’s Disease: A Critical Overview

Yahya

Fonzo

Monfrini

2023

IJMS

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Parkinson’s disease (PD) is the second most common neurodegenerative disorder in the aging population, and no disease-modifying therapy has been approved to date. The pathogenesis of PD has been related to many dysfunctional cellular mechanisms, however, most of its monogenic forms are caused by pathogenic variants in genes involved in endolysosomal function (LRRK2, VPS35, VPS13C, and ATP13A2) and synaptic vesicle trafficking (SNCA, RAB39B, SYNJ1, and DNAJC6). Moreover, an extensive search for PD risk variants revealed strong risk variants in several lysosomal genes (e.g., GBA1, SMPD1, TMEM175, and SCARB2) highlighting the key role of lysosomal dysfunction in PD pathogenesis. Furthermore, large genetic studies revealed that PD status is associated with the overall “lysosomal genetic burden”, namely the cumulative effect of strong and weak risk variants affecting lysosomal genes. In this context, understanding the complex mechanisms of impaired vesicular trafficking and dysfunctional endolysosomes in dopaminergic neurons of PD patients is a fundamental step to identifying precise therapeutic targets and developing effective drugs to modify the neurodegenerative process in PD.

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Section: Monogenic Causes Of Pd Associated With Endolysosomal and Ves...mentioning

confidence: 99%

Section: Monogenic Causes Of Pd Associated With Endolysosomal and Ves...mentioning

confidence: 99%

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Genetic Evidence for Endolysosomal Dysfunction in Parkinson’s Disease: A Critical Overview

Yahya

Fonzo

Monfrini

2023

IJMS

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“…However, even in the patients homozygous for mutations in GBA, the symptoms of parkinsonism develop only in some of mutation carriers regardless of the presence of the clinical phenotype of Gaucher disease. [111] Note. Year, year when pathogenetically significant mutation was first described.…”

Section: Monogenic Forms Of Parkinson's Diseasementioning

confidence: 99%

Genetic Architecture of Parkinson’s Disease

Шадрина

Slominsky

2023

Biochemistry Moscow

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Year 2022 marks 25 years since the first mutation in familial autosomal dominant Parkinson’s disease was identified. Over the years, our understanding of the role of genetic factors in the pathogenesis of familial and idiopathic forms of Parkinson’s disease has expanded significantly – a number of genes for the familial form of the disease have been identified, and DNA markers for an increased risk of developing its sporadic form have been found. But, despite all the success achieved, we are far from an accurate assessment of the contribution of genetic and, even more so, epigenetic factors to the disease development. The review summarizes the information accumulated to date on the genetic architecture of Parkinson’s disease and formulates issues that need to be addressed, which are primarily related to the assessment of epigenetic factors in the disease pathogenesis.

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“…LOF mutations in the lipid transport protein VPS13C result in autosomal recessive PD (Lesage et al, 2016 ; Darvish et al, 2018 ; Monfrini et al, 2022 ). More recently, mutations in VPS13C have also been linked to dementia with Lewy Bodies, underscoring common underlying molecular mechanisms in the spectrum of Lewy Body diseases (Smolders et al, 2021 ).…”

Section: Endoplasmic Reticulum-late Endosome/lysosome Contactsmentioning

confidence: 99%

Inter-organellar Communication in Parkinson's and Alzheimer's Disease: Looking Beyond Endoplasmic Reticulum-Mitochondria Contact Sites

et al. 2022

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Neurodegenerative diseases (NDs) are generally considered proteinopathies but whereas this may initiate disease in familial cases, onset in sporadic diseases may originate from a gradually disrupted organellar homeostasis. Herein, endolysosomal abnormalities, mitochondrial dysfunction, endoplasmic reticulum (ER) stress, and altered lipid metabolism are commonly observed in early preclinical stages of major NDs, including Parkinson's disease (PD) and Alzheimer's disease (AD). Among the multitude of underlying defective molecular mechanisms that have been suggested in the past decades, dysregulation of inter-organellar communication through the so-called membrane contact sites (MCSs) is becoming increasingly apparent. Although MCSs exist between almost every other type of subcellular organelle, to date, most focus has been put on defective communication between the ER and mitochondria in NDs, given these compartments are critical in neuronal survival. Contributions of other MCSs, notably those with endolysosomes and lipid droplets are emerging, supported as well by genetic studies, identifying genes functionally involved in lysosomal homeostasis. In this review, we summarize the molecular identity of the organelle interactome in yeast and mammalian cells, and critically evaluate the evidence supporting the contribution of disturbed MCSs to the general disrupted inter-organellar homeostasis in NDs, taking PD and AD as major examples.

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VPS13C-associated Parkinson's disease: Two novel cases and review of the literature

Cited by 13 publications

References 7 publications

Genetic Evidence for Endolysosomal Dysfunction in Parkinson’s Disease: A Critical Overview

Genetic Evidence for Endolysosomal Dysfunction in Parkinson’s Disease: A Critical Overview

Genetic Architecture of Parkinson’s Disease

Inter-organellar Communication in Parkinson's and Alzheimer's Disease: Looking Beyond Endoplasmic Reticulum-Mitochondria Contact Sites

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