KLEIN POSTERNACK, ANDRES DAVID
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KLEIN POSTERNACK, ANDRES DAVID
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andresklein@udd.cl
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46062217700

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2024 2024 2023 2023 2022 2022 2021 2021 2020 2020 2019 2019 2018 2018 0.0 0.0 0.5 0.5 1.0 1.0 1.5 1.5 2.0 2.0 2.5 2.5 3.0 3.0

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Publication

Is Parkinson's disease a lysosomal disorder?

2018 , KLEIN POSTERNACK, ANDRES DAVID , Joseph R Mazzulli

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Publication

Rare diseases in Chile: challenges and recommendations in universal health coverage context

2019 , Gonzalo Encina , CASTILLO LABORDE, CARLA CECILIA , LECAROS URZUA, JUAN ALBERTO , Karen Dubois-Camacho , CALDERON GIADROSIC, JUAN FRANCISCO , AGUILERA SANHUEZA, XIMENA PAZ , KLEIN POSTERNACK, ANDRES DAVID , REPETTO LISBOA, MARIA GABRIELA

AbstractRare diseases (RDs) are a large number of diverse conditions with low individual prevalence, but collectively may affect up to 3.5–5.9% of the population. They have psychosocial and economic impact on patients and societies, and are a significant problem for healthcare systems, especially for countries with limited resources. In Chile, financial protection exists for 20 known RDs through different programs that cover diagnosis and treatments. Although beneficial for a number of conditions, most RD patients are left without a proper legal structure that guarantees a financial coverage, and in a vulnerable situation. In this review, we present and analyze the main challenges of the Chilean healthcare system and legislation on RDs, and other ambits of the RD ecosystem, including patient advocacy groups and research. Finally, we propose a set of policy recommendations that includes creating a patient registry, eliciting social preferences on health and financial coverage, improving access to clinical genetic services and therapies, promoting research on RDs and establishing a Latin-American cooperation network, all aimed at promoting equitable quality healthcare access for people living with RDs.

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Publication

NPC1 as a Modulator of Disease Severity and Viral Entry of SARSCoV- 2

2021 , VIAL COX, MARIA CECILIA , CALDERON GIADROSIC, JUAN FRANCISCO , KLEIN POSTERNACK, ANDRES DAVID

The COVID-19 plague is hitting mankind. Several viruses, including SARS-CoV-1, MERS-CoV, EBOV, and SARS-CoV-2, use the endocytic machinery to enter the cell. Genomic variants in NPC1, which encodes for the endo-lysosomal Niemann-Pick type C1 protein, restricts the host-range of viruses in bats and susceptibility to infections in humans. Lack of NPC1 and its pharmacological suppression inhibits many viral infections including SARS-CoV-1 and Type I Feline Coronavirus Infection. Antiviral effects of NPC1-inhibiting drugs for COVID-19 treatment should be explored.

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Publication

Identification of genetic modifiers of murine hepatic β-glucocerebrosidase activity

2021 , Anyelo Durán , Boris Rebolledo-Jaramillo , Valeria Olguin , Marcelo Rojas-Herrera , Macarena Las Heras , CALDERON GIADROSIC, JUAN FRANCISCO , Silvana Zanlungo , David A. Priestman , Frances M. Platt , KLEIN POSTERNACK, ANDRES DAVID

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Publication

Controversies on the potential therapeutic use of rapamycin for treating a lysosomal cholesterol storage disease

2018 , CALDERON GIADROSIC, JUAN FRANCISCO , KLEIN POSTERNACK, ANDRES DAVID

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Finding pathogenic commonalities between Niemann-Pick type C and other lysosomal storage disorders: Opportunities for shared therapeutic interventions

2020 , M.J. Yañez , T. Marín , E. Balboa , KLEIN POSTERNACK, ANDRES DAVID , A.R. Alvarez , S. Zanlungo

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Publication

Modeling Parkinson’s Disease Heterogeneity to Accelerate Precision Medicine

2019 , Gonzalo H. Olivares , Patricio Olguín , KLEIN POSTERNACK, ANDRES DAVID

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Publication

Integrin Alpha E (CD103) Limits Virus-Induced IFN-I Production in Conventional Dendritic Cells

2021 , Vikas Duhan , Vishal Khairnar , Simo Kitanovski , Thamer A. Hamdan , KLEIN POSTERNACK, ANDRES DAVID , Judith Lang , Murtaza Ali , Tom Adomati , Hilal Bhat , Sarah-Kim Friedrich , Fanghui Li , Philippe Krebs , Anthony H. Futerman , Marylyn M. Addo , Cornelia Hardt , Daniel Hoffmann , Philipp A. Lang , Karl S. Lang

Early and strong production of IFN-I by dendritic cells is important to control vesicular stomatitis virus (VSV), however mechanisms which explain this cell-type specific innate immune activation remain to be defined. Here, using a genome wide association study (GWAS), we identified Integrin alpha-E (Itgae, CD103) as a new regulator of antiviral IFN-I production in a mouse model of vesicular stomatitis virus (VSV) infection. CD103 was specifically expressed by splenic conventional dendritic cells (cDCs) and limited IFN-I production in these cells during VSV infection. Mechanistically, CD103 suppressed AKT phosphorylation and mTOR activation in DCs. Deficiency in CD103 accelerated early IFN-I in cDCs and prevented death in VSV infected animals. In conclusion, CD103 participates in regulation of cDC specific IFN-I induction and thereby influences immune activation after VSV infection.

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Publication

c-Abl Inhibition Activates TFEB and Promotes Cellular Clearance in a Lysosomal Disorder

2020 , Pablo S. Contreras , Pablo J. Tapia , Lila González-Hódar , Ivana Peluso , Chiara Soldati , Gennaro Napolitano , Maria Matarese , Macarena Las Heras , Cristian Valls , Alexis Martinez , Elisa Balboa , Juan Castro , Nancy Leal , Frances M. Platt , Andrzej Sobota , Dominic Winter , KLEIN POSTERNACK, ANDRES DAVID , Diego L. Medina , Andrea Ballabio , Alejandra R. Alvarez , Silvana Zanlungo

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Publication

The lysosomal β-glucocerebrosidase strikes mitochondria: implications for Parkinson’s therapeutics

2024 , Juan Carlos Rubilar , Tiago Fleming Outeiro , KLEIN POSTERNACK, ANDRES DAVID

Abstract Parkinson’s disease is a neurodegenerative disorder primarily known for typical motor features that arise due to the loss of dopaminergic neurons in the substantia nigra. However, the precise molecular aetiology of the disease is still unclear. Several cellular pathways have been linked to Parkinson’s disease, including the autophagy-lysosome pathway, α-synuclein aggregation and mitochondrial function. Interestingly, the mechanistic link between GBA1, the gene that encodes for lysosomal β-glucocerebrosidase (GCase), and Parkinson’s disease lies in the interplay between GCase functions in the lysosome and mitochondria. GCase mutations alter mitochondria-lysosome contact sites. In the lysosome, reduced GCase activity leads to glycosphingolipid build-up, disrupting lysosomal function and autophagy, thereby triggering α-synuclein accumulation. Additionally, α-synuclein aggregates reduce GCase activity, creating a self-perpetuating cycle of lysosomal dysfunction and α-synuclein accumulation. GCase can also be imported into the mitochondria, where it promotes the integrity and function of mitochondrial complex I. Thus, GCase mutations that impair its normal function increase oxidative stress in mitochondria, the compartment where dopamine is oxidized. In turn, the accumulation of oxidized dopamine adducts further impairs GCase activity, creating a second cycle of GCase dysfunction. The oxidative state triggered by GCase dysfunction can also induce mitochondrial DNA damage which, in turn, can cause dopaminergic cell death. In this review, we highlight the pivotal role of GCase in Parkinson’s disease pathogenesis and discuss promising examples of GCase-based therapeutics, such as gene and enzyme replacement therapies, small molecule chaperones and substrate reduction therapies, among others, as potential therapeutic interventions.

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