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See detailNeurodegeneration and Neuroinflammation in Parkinson’s Disease: a Self-Sustained Loop
Arena, Giuseppe UL; Sharma, K.; Agyeah, Gideon UL et al

in Current Neurology and Neuroscience Reports (2022), 22(8), 427440

Purpose of Review: Neuroinflammation plays a significant role in Parkinson’s disease (PD) etiology along with mitochondrial dysfunction and impaired proteostasis. In this context, mechanisms related to ... [more ▼]

Purpose of Review: Neuroinflammation plays a significant role in Parkinson’s disease (PD) etiology along with mitochondrial dysfunction and impaired proteostasis. In this context, mechanisms related to immune response can act as modifiers at different steps of the neurodegenerative process and justify the growing interest in anti-inflammatory agents as potential disease-modifying treatments in PD. The discovery of inherited gene mutations in PD has allowed researchers to develop cellular and animal models to study the mechanisms of the underlying biology, but the original cause of neuroinflammation in PD is still debated to date. Recent Findings: Cell autonomous alterations in neuronal cells, including mitochondrial damage and protein aggregation, could play a role, but recent findings also highlighted the importance of intercellular communication at both local and systemic level. This has given rise to debate about the role of non-neuronal cells in PD and reignited intense research into the gut-brain axis and other non-neuronal interactions in the development of the disease. Whatever the original trigger of neuroinflammation in PD, what appears quite clear is that the aberrant activation of glial cells and other components of the immune system creates a vicious circle in which neurodegeneration and neuroinflammation nourish each other. Summary: In this review, we will provide an up-to-date summary of the main cellular alterations underlying neuroinflammation in PD, including those induced by environmental factors (e.g. the gut microbiome) and those related to the genetic background of affected patients. Starting from the lesson provided by familial forms of PD, we will discuss pathophysiological mechanisms linked to inflammation that could also play a role in idiopathic forms. Finally, we will comment on the potential clinical translatability of immunobiomarkers identified in PD patient cohorts and provide an update on current therapeutic strategies aimed at overcoming or preventing inflammation in PD. © 2022, The Author(s). [less ▲]

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See detailParkin Deficiency Impairs Mitochondrial DNA Dynamics and Propagates Inflammation.
Wasner, Kobi; Smajic, Semra UL; Ghelfi, Jenny UL et al

in Movement disorders : official journal of the Movement Disorder Society (2022)

BACKGROUND: Mutations in the E3 ubiquitin ligase parkin cause autosomal recessive Parkinson's disease (PD). Together with PTEN-induced kinase 1 (PINK1), parkin regulates the clearance of dysfunctional ... [more ▼]

BACKGROUND: Mutations in the E3 ubiquitin ligase parkin cause autosomal recessive Parkinson's disease (PD). Together with PTEN-induced kinase 1 (PINK1), parkin regulates the clearance of dysfunctional mitochondria. New mitochondria are generated through an interplay of nuclear- and mitochondrial-encoded proteins, and recent studies suggest that parkin influences this process at both levels. In addition, parkin was shown to prevent mitochondrial membrane permeability, impeding mitochondrial DNA (mtDNA) escape and subsequent neuroinflammation. However, parkin's regulatory roles independent of mitophagy are not well described in patient-derived neurons. OBJECTIVES: We sought to investigate parkin's role in preventing neuronal mtDNA dyshomeostasis, release, and glial activation at the endogenous level. METHODS: We generated induced pluripotent stem cell (iPSC)-derived midbrain neurons from PD patients with parkin (PRKN) mutations and healthy controls. Live-cell imaging, proteomic, mtDNA integrity, and gene expression analyses were employed to investigate mitochondrial biogenesis and genome maintenance. To assess neuroinflammation, we performed single-nuclei RNA sequencing in postmortem tissue and quantified interleukin expression in mtDNA/lipopolysaccharides (LPS)-treated iPSC-derived neuron-microglia co-cultures. RESULTS: Neurons from patients with PRKN mutations revealed deficits in the mitochondrial biogenesis pathway, resulting in mtDNA dyshomeostasis. Moreover, the energy sensor sirtuin 1, which controls mitochondrial biogenesis and clearance, was downregulated in parkin-deficient cells. Linking mtDNA disintegration to neuroinflammation, in postmortem midbrain with PRKN mutations, we confirmed mtDNA dyshomeostasis and detected an upregulation of microglia overexpressing proinflammatory cytokines. Finally, parkin-deficient neuron-microglia co-cultures elicited an enhanced immune response when exposed to mtDNA/LPS. CONCLUSIONS: Our findings suggest that parkin coregulates mitophagy, mitochondrial biogenesis, and mtDNA maintenance pathways, thereby protecting midbrain neurons from neuroinflammation and degeneration. © 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society. [less ▲]

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See detailPINK1 Protects against Staurosporine-Induced Apoptosis by Interacting with Beclin1 and Impairing Its Pro-Apoptotic Cleavage.
Brunelli, Francesco; Torosantucci, Liliana; Gelmetti, Vania et al

in Cells (2022), 11(4),

PINK1 is a causative gene for Parkinson's disease and the corresponding protein has been identified as a master regulator of mitophagy-the autophagic degradation of damaged mitochondria. It interacts with ... [more ▼]

PINK1 is a causative gene for Parkinson's disease and the corresponding protein has been identified as a master regulator of mitophagy-the autophagic degradation of damaged mitochondria. It interacts with Beclin1 to regulate autophagy and initiate autophagosome formation, even outside the context of mitophagy. Several other pro-survival functions of this protein have been described and indicate that it might play a role in other disorders, such as cancer and proliferative diseases. In this study, we investigated a novel anti-apoptotic function of PINK1. To do so, we used SH-SY5Y neuroblastoma cells, a neuronal model used in Parkinson's disease and cancer studies, to characterize the pro-survival functions of PINK1 in response to the apoptosis inducer staurosporine. In this setting, we found that staurosporine induces apoptosis but not mitophagy, and we demonstrated that PINK1 protects against staurosporine-induced apoptosis by impairing the pro-apoptotic cleavage of Beclin1. Our data also show that staurosporine-induced apoptosis is preceded by a phase of enhanced autophagy, and that PINK1 in this context regulates the switch from autophagy to apoptosis. PINK1 protein levels progressively decrease after treatment, inducing this switch. The PINK1-Beclin1 interaction is crucial in exerting this function, as mutants that are unable to interact do not show the anti-apoptotic effect. We characterized a new anti-apoptotic function of PINK1 that could provide options for treatment in proliferative or neurodegenerative diseases. [less ▲]

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See detailImpaired Mitochondrial-Endoplasmic Reticulum Interaction and Mitophagy in Miro1-Mutant Neurons in Parkinson’s Disease
Berenguer-Escuder, Clara; Grossmann, Dajana; Antony, Paul UL et al

in Human Molecular Genetics (2020)

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See detailMechanisms of neurodegeneration in Parkinson’s disease: keep neurons in the PINK1
Brunelli, Francesco UL; Valente, Enza Maria; Arena, Giuseppe UL

in Mechanisms of Ageing and Development (2020)

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See detailThe Emerging Role of RHOT1/Miro1 in the Pathogenesis of Parkinson's Disease.
Grossmann, Dajana; Berenguer-Escuder, Clara; Chemla, Axel UL et al

in Frontiers in neurology (2020), 11

The expected increase in prevalence of Parkinson's disease (PD) as the most common neurodegenerative movement disorder over the next years underscores the need for a better understanding of the underlying ... [more ▼]

The expected increase in prevalence of Parkinson's disease (PD) as the most common neurodegenerative movement disorder over the next years underscores the need for a better understanding of the underlying molecular pathogenesis. Here, first insights provided by genetics over the last two decades, such as dysfunction of molecular and organellar quality control, are described. The mechanisms involved relate to impaired intracellular calcium homeostasis and mitochondrial dynamics, which are tightly linked to the cross talk between the endoplasmic reticulum (ER) and mitochondria. A number of proteins related to monogenic forms of PD have been mapped to these pathways, i.e., PINK1, Parkin, LRRK2, and α-synuclein. Recently, Miro1 was identified as an important player, as several studies linked Miro1 to mitochondrial quality control by PINK1/Parkin-mediated mitophagy and mitochondrial transport. Moreover, Miro1 is an important regulator of mitochondria-ER contact sites (MERCs), where it acts as a sensor for cytosolic calcium levels. The involvement of Miro1 in the pathogenesis of PD was recently confirmed by genetic evidence based on the first PD patients with heterozygous mutations in RHOT1/Miro1. Patient-based cellular models from RHOT1/Miro1 mutation carriers showed impaired calcium homeostasis, structural alterations of MERCs, and increased mitochondrial clearance. To account for the emerging role of Miro1, we present a comprehensive overview focusing on the role of this protein in PD-related neurodegeneration and highlighting new developments in our understanding of Miro1, which provide new avenues for neuroprotective therapies for PD patients. [less ▲]

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See detailHuman Dopaminergic Neurons Lacking PINK1 Exhibit Disrupted Dopamine Metabolism Related to Vitamin B6 Co-Factors.
Bus, Christine; Zizmare, Laimdota; Feldkaemper, Marita et al

in iScience (2020), 23(12), 101797

PINK1 loss-of-function mutations cause early onset Parkinson disease. PINK1-Parkin mediated mitophagy has been well studied, but the relevance of the endogenous process in the brain is debated. Here, the ... [more ▼]

PINK1 loss-of-function mutations cause early onset Parkinson disease. PINK1-Parkin mediated mitophagy has been well studied, but the relevance of the endogenous process in the brain is debated. Here, the absence of PINK1 in human dopaminergic neurons inhibits ionophore-induced mitophagy and reduces mitochondrial membrane potential. Compensatory, mitochondrial renewal maintains mitochondrial morphology and protects the respiratory chain. This is paralleled by metabolic changes, including inhibition of the TCA cycle enzyme mAconitase, accumulation of NAD(+), and metabolite depletion. Loss of PINK1 disrupts dopamine metabolism by critically affecting its synthesis and uptake. The mechanism involves steering of key amino acids toward energy production rather than neurotransmitter metabolism and involves cofactors related to the vitamin B6 salvage pathway identified using unbiased multi-omics approaches. We propose that reduction of mitochondrial membrane potential that cannot be controlled by PINK1 signaling initiates metabolic compensation that has neurometabolic consequences relevant to Parkinson disease. [less ▲]

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