KLEIN POSTERNACK, ANDRES DAVID

Preferred name

Main Affiliation

Facultad de Medicina Clínica Alemana Universidad del Desarrollo

andresklein@udd.cl

ORCID

0000-0002-9951-2174

Scopus Author ID

46062217700

Goggle Scholar

https://scholar.google.com/citations?user=fGgQ6MIAAAAJ&hl=es&oi=ao

Now showing 1 - 10 of 19

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Dataset - Genomic modifiers of neurological resilience in a Niemann-Pick C family
(United States National Library of Medicine, 2025)
MACARENA ANDREA LAS HERAS PARRAGUEZ
;
BENJAMIN SZENFELD
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Olguín Araneda Valeria Alejandra
;
JUAN CARLOS RUBILAR ESPINOZA
;
CALDERON GIADROSIC, JUAN FRANCISCO
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Polygenic scores contribution to Parkinson’s disease comorbidities
(Oxford University Press (OUP), 2025)
Carlos F Hernández
;
Camilo Villaman
;
Cristian Tejos
;
REPETTO LISBOA, MARIA GABRIELA
;
Costin Leu
Comorbidities are common in Parkinson’s disease and significantly impact the disease progression and management. While polygenic scores have been widely used to assess genetic risk for complex diseases, their role in comorbidity presentation in Parkinson’s disease remains unclear. This study investigates whether genetic predisposition to comorbidities, as measured by polygenic scores, differs between individuals with Parkinson’s disease and the general population and explores how genetic risk influences disease onset and sex-related differences. We analysed data from 4144 individuals with Parkinson’s disease and 370 480 individuals from the general population in the UK Biobank, focusing on four comorbidities with high-quality genome-wide association study data: Type 2 diabetes, major depressive disorder, migraine headaches and epilepsy. We first compared polygenic score distributions between individuals with Parkinson’s disease and the general population. While our findings indicate that comorbidities and polygenic risk scores do not significantly differ between individuals with Parkinson’s disease and the general population, we show an association with disease onset and sex-specific differences. Individuals with earlier disease onset (50–70 years old) had higher genetic risk for major depressive disorder (odds ratio: 2.19, P-value: 1.27 × 10⁻¹⁵) and epilepsy (odds ratio: 1.58, P-value: 0.00845). Additionally, a female participant with Parkinson’s disease exhibited higher genetic risk scores for major depressive disorder (odds ratio: 1.5, P-value: 0.0119) and migraine headaches (odds ratio: 2.1, P-value: 0.0155), while a male participant displayed higher genetic risk scores for Type 2 diabetes (odds ratio: 2.7, P-value: 2.11 × 10⁻¹⁷). Comorbidity-polygenic score did not differ between people with versus without Parkinson’s disease, yet within Parkinson’s disease, a higher genetic burden for specific comorbidities was linked to earlier onset and sex-specific presentation, implicating common variants as modifiers of clinical heterogeneity rather than the primary disease risk. These results enhance our understanding of the genetic influences shaping the broader clinical presentation of Parkinson’s disease and highlight the need for further research into the interplay between genetic risk factors, comorbidities and disease heterogeneity.
Scopus© Citations 2 3
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Modeling Parkinson’s Disease Heterogeneity to Accelerate Precision Medicine
(2019)
Gonzalo H. Olivares
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Patricio Olguín
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KLEIN POSTERNACK, ANDRES DAVID
Scopus© Citations 7 3
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The lysosomal β-glucocerebrosidase strikes mitochondria: implications for Parkinson’s therapeutics
(2024)
Juan Carlos Rubilar
;
Tiago Fleming Outeiro
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KLEIN POSTERNACK, ANDRES DAVID
<jats:title>Abstract</jats:title> <jats:p>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.</jats:p>
Scopus© Citations 7 1
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c-Abl Inhibition Activates TFEB and Promotes Cellular Clearance in a Lysosomal Disorder
(2020)
Pablo S. Contreras
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Pablo J. Tapia
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Lila González-Hódar
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Ivana Peluso
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Chiara Soldati
Scopus© Citations 30 8
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Modifier gene identification reveals therapeutic pathways for adult and childhood dementias
(Springer Science and Business Media LLC, 2026-02-16)
Benjamín Szenfeld
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Macarena Las Heras
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Juan Carlos Rubilar
;
Leah Skura
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Jorge Olivares
2
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Is Parkinson's disease a lysosomal disorder?
(2018)
KLEIN POSTERNACK, ANDRES DAVID
;
Joseph R Mazzulli
35Scopus© Citations 149
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Integrin Alpha E (CD103) Limits Virus-Induced IFN-I Production in Conventional Dendritic Cells
(2021)
Vikas Duhan
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Vishal Khairnar
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Simo Kitanovski
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Thamer A. Hamdan
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KLEIN POSTERNACK, ANDRES DAVID
<jats:p>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 (<jats:italic>Itgae</jats:italic>, 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.</jats:p>
1Scopus© Citations 4
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Genomic modifiers of neurological resilience in a Niemann‐Pick C family
(Wiley, 2025-06-12)
Macarena Las Heras
;
Benjamín Szenfeld
;
Valeria Olguín
;
Juan Carlos Rubilar
;
CALDERON GIADROSIC, JUAN FRANCISCO
Niemann-Pick type C (NPC) disease, caused by NPC1 or NPC2 variants, disrupts cholesterol and glycolipid trafficking, leading to diverse clinical manifestations. To understand the genetic basis of neurological resilience, we analyzed an NPC family with variable phenotypes, identifying loss-of-function variants in CCDC115, SLC4A5, DEPDC5, ETFDH, SNRNP200, and DOCK1 that co-segregated with milder neurological involvement. Using yeast models, we successfully predicted NPC-like severity based on orthologous gene variants. RNA-seq revealed a positive correlation between mitochondrial transcripts and cellular fitness. Modeling NPC in yeast lacking the SLC4A5 ortholog, bor1, enhanced cellular fitness, improved mitochondrial function, and reduced sterol accumulation. Our findings identify potential modifiers and biomarkers of NPC severity, highlighting mitochondrial pathways and SLC4A5 as a therapeutic target.
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Gadolinium Chloride Rescues Niemann–Pick Type C Liver Damage
(2018)
KLEIN POSTERNACK, ANDRES DAVID
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Juan Oyarzún
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Cristian Cortez
;
Silvana Zanlungo
<jats:p>Niemann–Pick type C (NPC) disease is a rare neurovisceral cholesterol storage disorder that arises from loss of function mutations in the NPC1 or NPC2 genes. Soon after birth, some patients present with an aggressive hepatosplenomegaly and cholestatic signs. Histopathologically, the liver presents with large numbers of foam cells; however, their role in disease pathogenesis has not been explored in depth. Here, we studied the consequences of gadolinium chloride (GdCl3) treatment, a well-known Kupffer/foam cell inhibitor, at late stages of NPC liver disease and compared it with NPC1 genetic rescue in hepatocytes in vivo. GdCl3 treatment successfully blocked the endocytic capacity of hepatic Kupffer/foam measured by India ink endocytosis, decreased the levels CD68—A marker of Kupffer cells in the liver—and normalized the transaminase levels in serum of NPC mice to a similar extent to those obtained by genetic Npc1 rescue of liver cells. Gadolinium salts are widely used as magnetic resonance imaging (MRI) contrasts. This study opens the possibility of targeting foam cells with gadolinium or by other means for improving NPC liver disease. Synopsis: Gadolinium chloride can effectively rescue some parameters of liver dysfunction in NPC mice and its potential use in patients should be carefully evaluated.</jats:p>
Scopus© Citations 8 1

KLEIN POSTERNACK, ANDRES DAVID

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