bims-tofagi 2024-12-22 papers

Issue of 2024–12–22
six papers selected by
Michele Frison, University of Cambridge

Autophagy. 2024 Dec 19.

Parkinson disease (PD) is a neurodegenerative disease characterized by the loss of dopaminergic neurons in the substantia nigra, primarily due to mitochondria dysfunction. PRKN (parkin RBR E3 ubiquitin protein ligase) and PINK1 (PTEN induced kinase 1) are linked to early-onset cases of PD and essential for the clearance of damaged mitochondria via selective mitochondrial autophagy (mitophagy). In a recent publication, we detail how a small molecule can activate PRKN mutants that are unable to be phosphorylated, restoring mitophagy in cellular assays. These findings offer hope for the design of therapeutic drugs for some forms of PD.

Keywords: Activator; PARK2; mitochondria; neurodegeneration; parkinson disease; ubiquitin

DOI: https://doi.org/10.1080/15548627.2024.2443232

Cell Calcium. 2024 Dec 13. pii: S0143-4160(24)00144-1. [Epub ahead of print]125 102986

A role for lysosomal calcium channels in mitigating mitochondrial damage and oxidative stress.

Leandro C Clementino, Andrew P Thomas, Emily M Rocha, Sabine Hilfiker.

Elevated free fatty acids and oxidative stress may function as pathogenic factors in endothelial dysfunction that is associated with various cardiovascular complications. In recent work, Feng and colleagues report that activation of a lysosomal Ca2+ channel may be a viable option to alleviate oxidative damage by boosting lysosome biogenesis and mitophagy.

Keywords: Calcium signaling; Lysosome; Mitophagy; Reactive oxygen species; TFEB; TRPML1

DOI: https://doi.org/10.1016/j.ceca.2024.102986

Autophagy. 2024 Dec 19. 1-3

Dynamic mitophagy trajectories hallmark brain aging.

Anna Rappe, Thomas G McWilliams.

Studies using mitophagy reporter mice have established steady-state landscapes of mitochondrial destruction in mammalian tissues, sparking intense interest in basal mitophagy. Yet how basal mitophagy is modified by healthy aging in diverse brain cell types has remained a mystery. We present a comprehensive spatiotemporal analysis of mitophagy and macroautophagy dynamics in the aging mammalian brain, reporting critical region- and cell-specific turnover trajectories in a longitudinal study. We demonstrate that the physiological regulation of mitophagy in the mammalian brain is cell-specific, dynamic and complex. Mitophagy increases significantly in the cerebellum and hippocampus during midlife, while remaining unchanged in the prefrontal cortex (PFC). Conversely, macroautophagy decreases in the hippocampus and PFC, but remains stable in the cerebellum. We also describe emergent lysosomal heterogeneity, with subsets of differential acidified lysosomes accumulating in the aging brain. We further establish midlife as a critical inflection point for autophagy regulation, which may be important for region-specific vulnerability and resilience to aging. By mapping in vivo autophagy dynamics at the single cell level within projection neurons, interneurons and microglia, to astrocytes and secretory cells, we provide a new framework for understanding brain aging and offer potential targets and timepoints for further study and intervention in neurodegenerative diseases.

Keywords: Aging; autophagy; brain; mitochondria; mitophagy

DOI: https://doi.org/10.1080/15548627.2024.2426115

J Clin Invest. 2024 Dec 17. pii: e180478. [Epub ahead of print]

PINK1 is a target of T cell responses in Parkinson's disease.

Gregory P Williams, Antoine Freuchet, Tanner Michaelis, April Frazier, Ngan K Tran, João Rodrigues Lima-Junior, Elizabeth J Phillips, Simon A Mallal, Irene Litvan, Jennifer G Goldman, Roy N Alcalay, John Sidney, David Sulzer, Alessandro Sette, Cecilia S Lindestam Arlehamn.

Parkinson's disease (PD) is the second most prevalent neurodegenerative disorder. While there is no curative treatment, the immune system's involvement with autoimmune T cells that recognize the protein alpha-synuclein (α-syn) in a subset of individuals suggests new areas for therapeutic strategies. As not all patients with PD have T cells specific for α-syn, we explored additional autoantigenic targets of T cells in PD. We generated 15-mer peptides spanning several PD-related proteins implicated in PD pathology, including Glucosylceramidase Beta 1 (GBA), Superoxide dismutase 1 (SOD1), PTEN Induced Kinase 1 (PINK1), Parkin RBR E3 Ubiquitin Protein Ligase (parkin), Oxoglutarate Dehydrogenase (OGDH), and Leucine Rich Repeat Kinase 2 (LRRK2). Cytokine production (IFNγ, IL-5, IL-10) against these proteins was measured using a fluorospot assay and PBMCs from patients with PD and age-matched healthy controls. We identified PINK1, a regulator of mitochondrial stability, as an autoantigen targeted by T cells, as well as its unique epitopes, and their HLA restriction. The PINK1-specific T cell reactivity revealed sex-based differences as it was predominantly found in male patients with PD, which may contribute to the heterogeneity of PD. Identifying and characterizing PINK1 and other autoinflammatory targets may lead to antigen-specific diagnostics, progression markers, and/or novel therapeutic strategies for PD.

Keywords: Adaptive immunity; Autoimmunity; Immunology; Parkinson disease; T cells

DOI: https://doi.org/10.1172/JCI180478

Cold Spring Harb Perspect Med. 2024 Dec 18. pii: a041619. [Epub ahead of print]

Autophagy and Protein Quality Control in Parkinson's Disease.

Marta Martinez-Vicente, Miquel Vila.

Autophagy is a vital cellular process responsible for the degradation of proteins, organelles, and other cellular components within lysosomes. In neurons, basal autophagy is indispensable for maintaining cellular homeostasis and protein quality control. Accordingly, lysosomal dysfunction has been proposed to be associated with neurodegeneration, and with Parkinson's disease (PD) in particular. Aging, dopamine metabolism, and PD-linked genetic mutations are thought to impair the autophagic-lysosomal pathway, disrupt cellular proteostasis, and contribute to PD pathogenesis. These alterations represent an opportunity to identify potential new therapeutic targets and disease biomarkers, thus laying the groundwork for the development of novel disease-modifying strategies for PD that are aimed at restoring cellular proteostasis and quality control systems.

DOI: https://doi.org/10.1101/cshperspect.a041619

Aging Cell. 2024 Dec 15. e14449

Age-associated accumulation of RAB9 disrupts oocyte meiosis.

Min Gao, Fang Wang, Tengteng Xu, Yanling Qiu, Tianqi Cao, Simiao Liu, Wenlian Wu, Yitong Zhou, Haiying Liu, Fenghua Liu, Junjiu Huang.

The critical role of some RAB family members in oocyte meiosis has been extensively studied, but their role in oocyte aging remains poorly understood. Here, we report that the vesicle trafficking regulator, RAB9 GTPase, is essential for oocyte meiosis and aging in humans and mice. RAB9 was mainly located at the meiotic spindle periphery and cortex during oocyte meiosis. In humans and mice, we found that the RAB9 protein level were significantly increased in old oocytes. Age-related accumulation of RAB9 inhibits first polar body extrusion and reduces the developmental potential of oocytes. Further studies showed that increased Rab9 disrupts spindle formation and chromosome alignment. In addition, Rab9 overexpression disrupts the actin cap formation and reduces the cortical actin levels. Mechanically, Rab9-OE increases ROS levels, decreases mitochondrial membrane potential, ATP content and the mtDNA/nDNA ratio. Further studies showed that Rab9-OE activates the PINK1-PARKIN mitophagy pathway. Importantly, we found that reducing RAB9 protein expression in old oocytes could partially improve the rate of old oocyte maturation, ameliorate the accumulation of age-related ROS levels and spindle abnormalities, and partially rescue ATP levels, mtDNA/nDNA ratio, and PINK1 and PARKIN expression. In conclusion, our results suggest that RAB9 is required to maintain the balance between mitochondrial function and meiosis, and that reducing RAB9 expression is a potential strategy to ameliorate age-related deterioration of oocyte quality.

Keywords: RAB9; aging; meiosis; mitochondrial function; oocyte

DOI: https://doi.org/10.1111/acel.14449