Article
Neurosciences
Koray Kirimtay, Benan Temizci, Murat Gultekin, Zuhal Yapici, Arzu Karabay
Summary: Whole-exome sequencing identified a novel homozygous mutation in ATP13A2 in siblings with mixed neurological symptoms. This frameshift mutation led to degradation of ATP13A2 mRNA by nonsense-mediated decay, preventing the expression of ATP13A2 protein in the patients' fibroblasts. Iron accumulation in the absence of ATP13A2 protein and hypointense areas on T2-weighted images may suggest a broader spectrum of Kufor-Rakeb Syndrome as neurodegeneration with brain iron accumulation disorders.
Review
Biochemistry & Molecular Biology
Maxime Teixeira, Razan Sheta, Walid Idi, Abid Oueslati
Summary: The abnormal accumulation of alpha-synuclein into proteinaceous inclusions called Lewy bodies is a neuropathological hallmark of Parkinson's disease and related disorders. Emerging evidence suggests that dysfunction of the endolysosomal system may play a role in the formation of these inclusions. The interaction between alpha-synuclein aggregation and the endolysosomal system disruption is not fully understood, but it is a potential target for developing disease-modifying treatments for PD and related disorders.
Review
Biochemistry & Molecular Biology
Vidal Yahya, Alessio Di Fonzo, Edoardo Monfrini
Summary: Parkinson's disease is the second most common neurodegenerative disorder among aging individuals and lacks disease-modifying therapy. The pathogenesis of Parkinson's disease involves dysfunction in several cellular mechanisms, with many monogenic forms resulting from pathogenic variants in genes related to endolysosomal function and synaptic vesicle trafficking. Additionally, studies have found a strong association between Parkinson's disease and lysosomal genes, indicating the significant role of lysosomal dysfunction in disease development. Understanding the mechanisms behind impaired vesicular trafficking and dysfunctional endolysosomes in dopaminergic neurons is crucial for identifying therapeutic targets and developing effective drugs for modifying the neurodegenerative process.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2023)
Article
Biochemistry & Molecular Biology
Huiling Gao, Hehong Sun, Nan Yan, Pu Zhao, He Xu, Wei Zheng, Xiaoyu Zhang, Tao Wang, Chuang Guo, Manli Zhong
Summary: Zinc homeostasis imbalance is a major cause of Parkinson's disease, and ATP13A2 plays an important role in regulating zinc homeostasis and alpha-synuclein accumulation. High zinc ion treatment leads to reduced spatial exploration behavior in mice, increased phosphorylation levels of alpha-synuclein, inhibition of the autophagy pathway, and activation of apoptosis signaling pathways. Overexpression of ATP13A2 reverses these protein changes, while its knockout exacerbates alpha-synuclein phosphorylation.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2022)
Review
Neurosciences
Jessica K. Smith, George D. Mellick, Alex M. Sykes
Summary: Parkinson's disease (PD) is a chronic neurodegenerative disease characterized by loss of dopaminergic neurons. Protein trafficking and α-synuclein have been identified as major contributors to the death of these neurons. Recent research suggests that α-synuclein can propagate through the brain and form aggregates. Understanding the mechanisms of α-synuclein propagation and clearance is crucial for therapeutic strategies.
FRONTIERS IN CELLULAR NEUROSCIENCE
(2023)
Review
Neurosciences
Fan Zhang, Zhiwei Wu, Fei Long, Jieqiong Tan, Ni Gong, Xiaorong Li, Changwei Lin
Summary: This article summarizes the effects of ATP13A2 gene mutations on PD, discusses the molecular mechanism of lysosomal autophagy inhibition and abnormal alpha-synuclein accumulation, and provides a new direction for future research on the pathogenesis and therapeutic targets of ATP13A2 gene-related PD.
FRONTIERS IN CELLULAR NEUROSCIENCE
(2022)
Article
Multidisciplinary Sciences
Takuto Fujii, Shushi Nagamori, Pattama Wiriyasermkul, Shizhou Zheng, Asaka Yago, Takahiro Shimizu, Yoshiaki Tabuchi, Tomoyuki Okumura, Tsutomu Fujii, Hiroshi Takeshima, Hideki Sakai
Summary: Mutations in the human ATP13A2 gene are associated with the development of Parkinson's disease. This study reveals that ATP13A2 acts as a H+/K+ transporting protein in lysosomes, which prevents alkalization of lysosomes and accumulation of alpha-synuclein.
NATURE COMMUNICATIONS
(2023)
Article
Biochemistry & Molecular Biology
Sue Im Sim, Eunyong Park
Summary: P5A- and P5B- ATPases, also known as P5-ATPases, are specific ATP-dependent transporters in eukaryotes that play important roles in the functions of the endoplasmic reticulum and endo-/lysosomes. Recent studies using cryo-electron microscopy and biochemistry have revealed the substrate specificities and transport mechanisms of P5-ATPases, which are distinct from other members of the P-type ATPase superfamily. P5A-ATPases are involved in protein quality control by extracting mistargeted or mis-inserted transmembrane helices from the ER membrane, while P5B-ATPases mediate the export of polyamines from late endo-/lysosomes to the cytosol. Structural analysis of yeast and human P5-ATPases has provided insights into their substrate recognition and transport mechanisms, highlighting the unique adaptation of the P5-ATPase subfamily for transporting atypical substrates.
CURRENT OPINION IN STRUCTURAL BIOLOGY
(2023)
Article
Clinical Neurology
Naveen Kumar Bhardwaj, Vykuntaraju K. Gowda, Jitendra Saini, Ashwin Vivek Sardesai, Rashmi Santhoshkumar, Anita Mahadevan
Summary: This study retrospectively analyzed the clinical, radiological, and genetic data of 27 NBIA patients in a tertiary care center in Southern India from 2014 to 2020, finding that PLAN and PKAN were the most common types. Common symptoms included walking difficulty, developmental regression, and epilepsy, with pyramidal signs being the most common examination feature.
BRAIN & DEVELOPMENT
(2021)
Review
Biochemistry & Molecular Biology
Maria Andres-Alonso, Michael R. Kreutz, Anna Karpova
Summary: The complex morphology and functional demands of neurons pose a challenge for proteostasis, particularly at presynaptic sites. Efficient mechanisms are required to ensure protein turnover between the cell body and synapses and to maintain synaptic function.
CELLULAR AND MOLECULAR LIFE SCIENCES
(2021)
Article
Neurosciences
Maria Izco, Estefania Carlos, Lydia Alvarez-Erviti
Summary: Endolysosomal dysfunction plays a critical role in the pathogenesis of neurodegenerative diseases, affecting the generation and transmission of exosomes, which are involved in the spread of pathological proteins or neuroinflammatory factors related to neurodegenerative diseases.
NEUROBIOLOGY OF DISEASE
(2022)
Article
Neurosciences
Maria Sanchiz-Calvo, Eduard Bentea, Veerle Baekelandt
Summary: Genes associated with endolysosomal function have been found to increase the risk of Parkinson's disease. Rodent models have been created to study the role of these genes in disease development and have shown parkinsonian features related to endolysosomal dysfunction. These animal models provide insights into the contribution of endolysosomal dysfunction in Parkinson's disease and can be used for testing therapeutic approaches.
CURRENT OPINION IN NEUROBIOLOGY
(2022)
Article
Biochemistry & Molecular Biology
Sue Im Sim, Soren von Bulow, Gerhard Hummer, Eunyong Park
Summary: Polyamines are small, organic polycations essential to all forms of life. Recent studies suggest that ATP13A2 and its close homologs are polyamine transporters at endo-/lysosomes. High-resolution cryoelectron microscopy structures of ATP13A2 revealed a near-complete transport cycle and the basis for polyamine specificity.
Review
Biochemistry & Molecular Biology
Daniella Cesar-Silva, Filipe S. Pereira-Dutra, Ana Lucia Moraes Giannini, Cecilia Jacques G. de Almeida
Summary: This article describes and discusses the various functions of the endolysosomal system, including homeostasis and its role during viral infections. The authors highlight that pathogens have evolved strategies to avoid and manipulate lysosomal function in order to survive and reproduce.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2022)
Article
Biochemistry & Molecular Biology
Jianmin Si, Chris van den Haute, Evy Lobbestael, Shaun Martin, Sarah van Veen, Peter Vangheluwe, Veerle Baekelandt
Summary: ATP13A2 loss impairs lysosomal membrane integrity and induces alpha-synuclein multimerization, while overexpression has a protective effect on alpha-synuclein by promoting ubiquitin-proteasome system activity and reducing alpha syn membrane association. Additionally, ATP13A2 promotes the secretion of alpha-synuclein through nanovesicles, suggesting a regulatory function independent of ATPase and transport activity.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2021)
Article
Neurosciences
Vikram G. Shakkottai, Amit Batla, Kailash Bhatia, William T. Dauer, Christian Dresel, Martin Niethammer, David Eidelberg, Robert S. Raike, Yoland Smith, H. A. Jinnah, Ellen J. Hess, Sabine Meunier, Mark Hallett, Rachel Fremont, Kamran Khodakhah, Mark S. LeDoux, Traian Popa, Cecile Gallea, Stephane Lehericy, Andreea C. Bostan, Peter L. Strick
Article
Biochemistry & Molecular Biology
Ji-Yeon Shin, Ivan Mendez-Lopez, Mingi Hong, Yuexia Wang, Kurenai Tanji, Wei Wu, Leana Shugol, Robert S. Krauss, William T. Dauer, Howard J. Worman
HUMAN MOLECULAR GENETICS
(2017)
Article
Biochemistry & Molecular Biology
Samuel S. Pappas, Chun-Chi Liang, Sumin Kim, CheyAnne O. Rivera, William T. Dauer
HUMAN MOLECULAR GENETICS
(2018)
Article
Cell Biology
Cosmo A. Saunders, Nathan J. Harris, Patrick T. Willey, Brian M. Woolums, Yuexia Wang, Alex J. McQuown, Amy Schoenhofen, Howard J. Worman, William T. Dauer, Gregg G. Gundersen, G. W. Gant Luxton
JOURNAL OF CELL BIOLOGY
(2017)
Article
Neurosciences
Jesse C. DeSimone, Samuel S. Pappas, Marcelo Febo, Roxana G. Burciu, Priyank Shukla, Luis M. Colon-Perez, William T. Dauer, David E. Vaillancourt
NEUROBIOLOGY OF DISEASE
(2017)
Article
Multidisciplinary Sciences
Chao Gao, Hanbo Sun, Tuo Wang, Ming Tang, Nicolaas I. Bohnen, Martijn L. T. M. Muller, Talia Herman, Nir Giladi, Alexandr Kalinin, Cathie Spino, William Dauer, Jeffrey M. Hausdorff, Ivo D. Dinov
SCIENTIFIC REPORTS
(2018)
Article
Multidisciplinary Sciences
Nasia Antoniou, Dimitrios Vlachakis, Anna Memou, Emmanouela Leandrou, Polytimi-Eleni Valkimadi, Katerina Melachroinou, Diane B. Re, Serge Przedborski, William T. Dauer, Leonidas Stefanis, Hardy J. Rideout
SCIENTIFIC REPORTS
(2018)
Article
Biology
Samuel S. Pappas, Jay Li, Tessa M. LeWitt, Jeong-Ki Kim, Umrao R. Monani, William T. Dauer
Article
Medicine, Research & Experimental
Ji-Yeon Shin, Antonio Hernandez-Ono, Tatyana Fedotova, Cecilia Ostlund, Michael J. Lee, Sarah B. Gibeley, Chun-Chi Liang, William T. Dauer, Henry N. Ginsberg, Howard J. Worman
JOURNAL OF CLINICAL INVESTIGATION
(2019)
Article
Biology
Jay Li, Chun-Chi Liang, Samuel S. Pappas, William T. Dauer
Article
Medicine, Research & Experimental
Jay Li, Daniel S. Levin, Audrey J. Kim, Samuel S. Pappas, William T. Dauer
Summary: Research in a mouse model of DYT1 dystonia showed a critical requirement for torsinA in normal motor function and gene therapy, with a particular emphasis on its essential role during a developmental critical period. These findings suggest that torsinA-based therapeutic strategies need to be employed early in the course of DYT1 dystonia for effectiveness.
JOURNAL OF CLINICAL INVESTIGATION
(2021)
Article
Multidisciplinary Sciences
Dhananjay Yellajoshyula, Samuel S. Pappas, Abigail E. Rogers, Biswa Choudhury, Xylena Reed, Jinhui Ding, Mark R. Cookson, Vikram G. Shakkottai, Roman J. Giger, William T. Dauer
Summary: THAP1 regulates myelination initiation by modulating GAG catabolism and ECM composition, with a lack of THAP1 leading to excess GAG accumulation and inhibition of OL maturation.
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
(2021)
Review
Clinical Neurology
Dhananjay Yellajoshyula, Samuel S. Pappas, William T. Dauer
Summary: The development of genomics and neuroimaging techniques has shed light on the importance of neuronal-glial interactions and extracellular matrix in nervous system development, function, and plasticity. Abnormalities in neuronal-glial interactions play a key role in neurodevelopmental disorders.
MOVEMENT DISORDERS
(2022)
Article
Biochemistry & Molecular Biology
Cecilia Ostlund, Antonio Hernandez-Ono, Samantha J. Turk, William T. Dauer, Henry N. Ginsberg, Howard J. Worman, Ji-Yeon Shin
Summary: In this study, the occurrence of nuclear lipid droplets (LDs) in primary hepatocytes from mice following depletion of lamina-associated polypeptide 1 (LAP1) was investigated. The results revealed that LAP1-depleted hepatocytes contain frequent nuclear LDs, which differ from cytoplasmic LDs in their associated proteins. The study also demonstrated a relationship of LD formation with nutritional state.
JOURNAL OF LIPID RESEARCH
(2022)
Article
Cell Biology
Dhananjay Yellajoshyula, Chun-Chi Liang, Samuel S. Pappas, Silvia Penati, Angela Yang, Rodan Mecano, Ravindran Kumaran, Stephanie Jou, Mark R. Cookson, William T. Dauer
DEVELOPMENTAL CELL
(2017)