Genetics and Pathogenesis of Parkinson's Syndrome

Annual Review of Pathology Mechanisms of Disease, Год журнала: 2022, Номер 18(1), С. 95 - 121

Опубликована: Сен. 13, 2022

Parkinson's disease (PD) is clinically, pathologically, and genetically heterogeneous, resisting distillation to a single, cohesive disorder. Instead, each affected individual develops virtually unique form of syndrome. Clinical manifestations consist variable motor nonmotor features, myriad overlaps are recognized with other neurodegenerative conditions. Although most commonly characterized by alpha-synuclein protein pathology throughout the central peripheral nervous systems, distribution varies pathologies modify PD or trigger similar manifestations. Nearly all influenced. More than 100 genes genetic loci have been identified, cases likely arise from interactions among many common rare variants. Despite its complex architecture, insights experimental dissection coalesce reveal unifying biological themes, including synaptic, lysosomal, mitochondrial, andimmune-mediated mechanisms pathogenesis. This emerging understanding syndrome, coupled advances in biomarkers targeted therapies, presages successful precision medicine strategies.

Язык: Английский

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Lipid droplets in the nervous system

The Journal of Cell Biology, Год журнала: 2021, Номер 220(7)

Опубликована: Июнь 21, 2021

Lipid droplets are dynamic intracellular lipid storage organelles that respond to the physiological state of cells. In addition controlling cell metabolism, they play a protective role for many cellular stressors, including oxidative stress. Despite prior descriptions appearing in brain as early century ago, only recently has cells found begun be understood. droplet functions have now been described nervous system context development, aging, and an increasing number neuropathologies. Here, we review basic mechanisms formation, turnover, function discuss how these enable different types under healthy pathological conditions.

Язык: Английский

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STING mediates neurodegeneration and neuroinflammation in nigrostriatal α-synucleinopathy

Proceedings of the National Academy of Sciences, Год журнала: 2022, Номер 119(15)

Опубликована: Апрель 8, 2022

In idiopathic Parkinson’s disease (PD), pathologic αSyn aggregates drive oxidative and nitrative stress that may cause genomic mitochondrial DNA damage. These events are associated with activation of the cyclic GMP-AMP synthase (cGAS)/stimulator interferon genes (STING) immune pathway, but it is not known whether STING activated in or contributes to α-synucleinopathies. Herein, we used primary cell cultures intrastriatal preformed fibril (αSyn-PFF) mouse model PD demonstrate pathology causes STING-dependent neuroinflammation dopaminergic neurodegeneration. microglia-astrocyte cultures, αSyn-PFFs induced double-strand break (DSB) damage response signaling (γH2A.X), as well TBK1 was blocked by inhibition. αSyn-PFF model, similarly observed increased γH2A.X within striatal microglia prior onset Using STING-deficient (Stinggt) mice, demonstrated α-Syn PFF STING-dependent. Furthermore, Stinggt mice were protected from PFF-induced motor deficits, accumulation, neuron loss. We also upregulation protein substantia nigra pars compacta (SNpc) human patients correlated significantly accumulation. upregulated treated αSyn-PFFs, which primed pathway mount stronger responses when exposed a agonist. Our results suggest microglial both neurodegeneration arising α-synucleinopathies, including PD.

Язык: Английский

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Monogenic Parkinson’s Disease: Genotype, Phenotype, Pathophysiology, and Genetic Testing

Genes, Год журнала: 2022, Номер 13(3), С. 471 - 471

Опубликована: Март 7, 2022

Parkinson’s disease may be caused by a single pathogenic variant (monogenic) in 5–10% of cases, but investigation these disorders provides valuable pathophysiological insights. In this review, we discuss each genetic form with focus on genotype, phenotype, pathophysiology, and the geographic ethnic distribution. Well-established genes include autosomal dominant forms (SNCA, LRRK2, VPS35) recessive (PRKN, PINK1 DJ1). Furthermore, mutations GBA gene are key risk factor for disease, there have been major developments X-linked dystonia parkinsonism. Moreover, atypical or complex parkinsonism due to such as ATP13A2, DCTN1, DNAJC6, FBXO7, PLA2G6, SYNJ1. numerous recently implicated CHCHD2, LRP10, TMEM230, UQCRC1, VPS13C. Additionally, role heterozygous genes, effect having two outcome deep brain stimulation, testing. We highlight that monogenic is influenced ethnicity geographical differences, reinforcing need global efforts pool large numbers patients identify novel candidate genes.

Язык: Английский

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Orchestration of selective autophagy by cargo receptors

Current Biology, Год журнала: 2022, Номер 32(24), С. R1357 - R1371

Опубликована: Дек. 1, 2022

Cellular homeostasis requires the swift and specific removal of damaged material. Selective autophagy represents a major pathway for degradation such cargo This is achieved by sequestration within double-membrane vesicles termed autophagosomes, which form de novo around subsequently deliver their content to lysosomes degradation. The importance selective exemplified various neurodegenerative diseases associated with defects in this pathway, including Parkinson's disease, amyotrophic lateral sclerosis, frontotemporal dementia. It has become evident that receptors are acting as Swiss army knives recognizing cargo, orchestrating recruitment machinery autophagosome biogenesis, closely aligning membrane cargo. Furthermore, sequester ubiquitinated proteins into larger condensates upstream induction. Here, we review recent insights mechanisms action focusing on roles sequestosome-like misfolded, mitochondria. We also highlight at steps function result accumulation harmful material how knowledge may guide design future therapies.

Язык: Английский

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Structural basis for ATG9A recruitment to the ULK1 complex in mitophagy initiation

Science Advances, Год журнала: 2023, Номер 9(7)

Опубликована: Фев. 15, 2023

The assembly of the autophagy initiation machinery nucleates autophagosome biogenesis, including in PINK1- and Parkin-dependent mitophagy pathway implicated Parkinson's disease. structural interaction between sole transmembrane protein, autophagy-related protein 9A (ATG9A), components Unc-51-like activating kinase (ULK1) complex is one major missing links needed to complete a map initiation. We determined 2.4-Å x-ray crystallographic structure ternary ATG9A carboxyl-terminal tail bound ATG13:ATG101 Hop1/Rev7/Mad2 (HORMA) dimer, which part ULK1 complex. term interacting portion extreme "HORMA dimer-interacting region" (HDIR). This shows that HDIR binds HORMA domain ATG101 by β sheet complementation such resides deep cleft at interface. Disruption this cells impairs damage-induced PINK1/Parkin mediated cargo receptor NDP52.

Язык: Английский

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Polyamines in Parkinson's Disease: Balancing Between Neurotoxicity and Neuroprotection

Annual Review of Biochemistry, Год журнала: 2023, Номер 92(1), С. 435 - 464

Опубликована: Апрель 5, 2023

The polyamines putrescine, spermidine, and spermine are abundant polycations of vital importance in mammalian cells. Their cellular levels tightly regulated by degradation synthesis, as well uptake export. Here, we discuss the delicate balance between neuroprotective neurotoxic effects context Parkinson's disease (PD). Polyamine decline with aging altered patients PD, whereas recent mechanistic studies on ATP13A2 (PARK9) demonstrated a driving role disturbed polyamine homeostasis PD. Polyamines affect pathways PD pathogenesis, such α-synuclein aggregation, influence PD-related processes like autophagy, heavy metal toxicity, oxidative stress, neuroinflammation, lysosomal/mitochondrial dysfunction. We formulate outstanding research questions regarding their potential biomarkers, possible therapeutic strategies for targeting homeostasis.

Язык: Английский

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Parkinson’s Disease

New England Journal of Medicine, Год журнала: 2024, Номер 391(5), С. 442 - 452

Опубликована: Июль 31, 2024

Parkinson's disease is a multisystem neurodegenerative disorder with motor and prominent, sometimes premonitory, nonmotor symptoms. Detection of gene variants may inform prognosis and, potentially, treatment.

Язык: Английский

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Pathogenesis of DJ-1/PARK7-Mediated Parkinson’s Disease

Cells, Год журнала: 2024, Номер 13(4), С. 296 - 296

Опубликована: Фев. 6, 2024

Parkinson’s disease (PD) is a common movement disorder associated with the degeneration of dopaminergic neurons in substantia nigra pars compacta. Mutations PD-associated gene PARK7 alter structure and function encoded protein DJ-1, resulting autosomal recessively inherited increases risk developing PD. DJ-1 was first discovered 1997 as an oncogene early-onset PD 2003. account for approximately 1% all occurrences, functions have been studied extensively. In healthy subjects, acts antioxidant oxidative stress sensor several neuroprotective mechanisms. It also involved mitochondrial homeostasis, regulation apoptosis, chaperone-mediated autophagy (CMA), dopamine homeostasis by regulating various signaling pathways, transcription factors, molecular chaperone functions. While protects against damaging reactive oxygen species, neurotoxins, mutant α-synuclein, mutations may lead to inefficient neuroprotection progression As current therapies treat only symptoms PD, development that directly inhibit stress-induced neuronal cell death critical. has proposed potential therapeutic target, while oxidized could operate biomarker this paper, we review role pathogenesis highlighting some its key consequences dysfunction.

Язык: Английский

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A mutational atlas for Parkin proteostasis

Nature Communications, Год журнала: 2024, Номер 15(1)

Опубликована: Фев. 20, 2024

Abstract Proteostasis can be disturbed by mutations affecting folding and stability of the encoded protein. An example is ubiquitin ligase Parkin, where gene variants result in autosomal recessive Parkinsonism. To uncover pathological mechanism provide comprehensive genotype-phenotype information, variant abundance massively parallel sequencing (VAMP-seq) leveraged to quantify Parkin cultured human cells. The resulting mutational map, covering 9219 out 9300 possible single-site amino acid substitutions nonsense variants, shows that most low are proteasome targets located within structured domains Half known disease-linked found at abundance. Systematic mapping degradation signals (degrons) reveals an exposed degron region proximal so-called “activation element”. This work provides examples how missense may cause either via destabilization native protein, or introducing local for degradation.

Язык: Английский

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