PINK1 phosphorylates ubiquitin predominantly in astrocytes

Barodia, Sandeep Kumar; McMeekin, Laura J.; Creed, Rose B.; Quinones, Elijah K; Cowell, Rita M.; Goldberg, Matthew S.

doi:10.1038/s41531-019-0101-9

Cited by 36 publications

(30 citation statements)

References 49 publications

(60 reference statements)

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“…While the high penetrance of PINK1 mutations establish its critical function for maintaining neurons the activity of PINK1 in primary neurons has been difficult to detect. However, Barodia et al determined the levels of PINK1 in neurons, astrocytes, microglia, and oligodendrocyte progenitor cells (OPCs) cultured from wild type and PINK1 knockout rat pups and showed that PINK1-dependent ubiquitin phosphorylation is predominately in astrocytes suggesting that the contribution of astrocyte dysfunction to PD pathogenesis warrants further investigation ( 45 ).…”

Section: Astrocytes and Their Role In Parkinson's Diseasementioning

confidence: 99%

The Pathogenesis of Parkinson's Disease: A Complex Interplay Between Astrocytes, Microglia, and T Lymphocytes?

et al. 2021

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Parkinson's disease (PD), the second most common neurodegenerative disease, is characterised by the motor symptoms of bradykinesia, rigidity and resting tremor and non-motor symptoms of sleep disturbances, constipation, and depression. Pathological hallmarks include neuroinflammation, degeneration of dopaminergic neurons in the substantia nigra pars compacta, and accumulation of misfolded α-synuclein proteins as intra-cytoplasmic Lewy bodies and neurites. Microglia and astrocytes are essential to maintaining homeostasis within the central nervous system (CNS), including providing protection through the process of gliosis. However, dysregulation of glial cells results in disruption of homeostasis leading to a chronic pro-inflammatory, deleterious environment, implicated in numerous CNS diseases. Recent evidence has demonstrated a role for peripheral immune cells, in particular T lymphocytes in the pathogenesis of PD. These cells infiltrate the CNS, and accumulate in the substantia nigra, where they secrete pro-inflammatory cytokines, stimulate surrounding immune cells, and induce dopaminergic neuronal cell death. Indeed, a greater understanding of the integrated network of communication that exists between glial cells and peripheral immune cells may increase our understanding of disease pathogenesis and hence provide novel therapeutic approaches.

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Section: Astrocytes and Their Role In Parkinson's Diseasementioning

confidence: 99%

The Pathogenesis of Parkinson's Disease: A Complex Interplay Between Astrocytes, Microglia, and T Lymphocytes?

et al. 2021

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“…Considering the roles for α-synuclein in synaptic function in normal and pathological states, investigators often use two-hit models to explore potential synergistic interactions between α-synuclein dysfunction and genes associated with increased risk for PD. However, in light of studies demonstrating roles for PD risk genes in non-neuronal populations (Moehle et al, 2012 ; Booth et al, 2017 ; Sliter et al, 2018 ; Barodia et al, 2019 ), it is important to consider whether genes of interest are expressed in the same cell types in vivo before exploring their potential interactions. With the recent emergence of single-cell RNA sequencing technologies, it is now possible to explore the neuroanatomical colocalization of genes using publicly accessible databases (Saunders et al, 2018 ; Zeisel et al, 2018 ; Monzón-Sandoval et al, 2020 ; Yuste et al, 2020 ).…”

Section: Potential Mechanisms Contributing To Synapse Loss In Pdmentioning

confidence: 99%

Molecular Mechanisms Underlying Synaptic and Axon Degeneration in Parkinson’s Disease

Gcwensa

Russell

Cowell

et al. 2021

Front. Cell. Neurosci.

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Parkinson’s disease (PD) is a progressive neurodegenerative disease that impairs movement as well as causing multiple other symptoms such as autonomic dysfunction, rapid eye movement (REM) sleep behavior disorder, hyposmia, and cognitive changes. Loss of dopamine neurons in the substantia nigra pars compacta (SNc) and loss of dopamine terminals in the striatum contribute to characteristic motor features. Although therapies ease the symptoms of PD, there are no treatments to slow its progression. Accumulating evidence suggests that synaptic impairments and axonal degeneration precede neuronal cell body loss. Early synaptic changes may be a target to prevent disease onset and slow progression. Imaging of PD patients with radioligands, post-mortem pathologic studies in sporadic PD patients, and animal models of PD demonstrate abnormalities in presynaptic terminals as well as postsynaptic dendritic spines. Dopaminergic and excitatory synapses are substantially reduced in PD, and whether other neuronal subtypes show synaptic defects remains relatively unexplored. Genetic studies implicate several genes that play a role at the synapse, providing additional support for synaptic dysfunction in PD. In this review article we: (1) provide evidence for synaptic defects occurring in PD before neuron death; (2) describe the main genes implicated in PD that could contribute to synapse dysfunction; and (3) show correlations between the expression of Snca mRNA and mouse homologs of PD GWAS genes demonstrating selective enrichment of Snca and synaptic genes in dopaminergic, excitatory and cholinergic neurons. Altogether, these findings highlight the need for novel therapeutics targeting the synapse and suggest that future studies should explore the roles for PD-implicated genes across multiple neuron types and circuits.

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“…Other studies have shown that PINK1 deficiency impairs both the formation of GFAP + - astrocytes during development and the proliferation of astrocytes upon stimulation with epidermal growth factor (EGF) or fetal bovine serum [ 143 ]. Recently, Barodia et al [ 108 ] found that PINK1-dependent ubiquitin phosphorylation is predominantly in astrocytes as compared to neuronal and other non-neuronal cell types, supporting the contribution astrocyte dysfunction to PD pathogenesis.…”

Section: Gene-environment Interactions Converge In the Modulation Of mentioning

confidence: 98%

“…Accumulating evidence indicates the expression of mutated genes, including SNCA , PRKN , PINK1 , DJ-1 , and LRRK2 in astrocytes and/or microglial cells and their implication in glial biology [22,106–112]. Importantly, the pathways regulated by these genes intersect the key cellular functions affected in Parkinson's disease, namely, the inflammatory response, endoplassmic reticulum (ER) stress, mitochondrial, lysosomal, proteosomal, autophagic and Wnt signaling functions [ [106] , [107] , [108] , [109] , [110] , [111] , [112] , [113] , [114] , [115] , [116] , [117] , [118] , [119] , [120] , [121] , [122] ]. Supporting evidence also come from genome-wide (GWA) and genome wide methylation data analysis, further suggesting that immune, mitochondrial and Wnt signaling pathways are associated not only with PD risk but also with PD progression [ [123] , [124] , [125] , [126] , [127] ] Strikingly, VPS35 gene located at 16q13-q21 chromosomal position and the two pathways, the Wnt signaling pathway, and retromer-mediated DMT1 missorting are proposed for the basis of VPS35 related PD [ 117 , 118 ].…”

Section: Gene-environment Interactions Converge In the Modulation Of mentioning

confidence: 99%

Nrf2/Wnt resilience orchestrates rejuvenation of glia-neuron dialogue in Parkinson's disease

Marchetti

2020

Redox Biology

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Oxidative stress and inflammation have long been recognized to contribute to Parkinson's disease (PD), a common movement disorder characterized by the selective loss of midbrain dopaminergic neurons (mDAn) of the substantia nigra pars compacta (SNpc). The causes and mechanisms still remain elusive, but a complex interplay between several genes and a number of interconnected environmental factors, are chiefly involved in mDAn demise, as they intersect the key cellular functions affected in PD, such as the inflammatory response, mitochondrial, lysosomal, proteosomal and autophagic functions. Nuclear factor erythroid 2 -like 2 ( NFE2L2/Nrf2 ), the master regulator of cellular defense against oxidative stress and inflammation, and Wingless ( Wnt ) /β-catenin signaling cascade, a vital pathway for mDAn neurogenesis and neuroprotection, emerge as critical intertwinned actors in mDAn physiopathology, as a decline of an Nrf2/Wnt/β-catenin prosurvival axis with age underlying PD mutations and a variety of noxious environmental exposures drive PD neurodegeneration. Unexpectedly, astrocytes, the so-called “ star-shaped ” cells, harbouring an arsenal of “beneficial” and “harmful” molecules represent the turning point in the physiopathological and therapeutical scenario of PD. Fascinatingly, “ astrocyte's fil rouge” brings back to Nrf2/Wnt resilience, as boosting the Nrf2/Wnt resilience program rejuvenates astrocytes, in turn (i) mitigating nigrostriatal degeneration of aged mice, (ii) reactivating neural stem progenitor cell proliferation and neuron differentiation in the brain and (iii) promoting a beneficial immunomodulation via bidirectional communication with mDAns. Then, through resilience of Nrf2/Wnt/β-catenin anti-ageing, prosurvival and proregenerative molecular programs, it seems possible to boost the inherent endogenous self-repair mechanisms. Here, the cellular and molecular aspects as well as the therapeutical options for rejuvenating glia-neuron dialogue will be discussed together with major glial-derived mechanisms and therapies that will be fundamental to the identification of novel diagnostic tools and treatments for neurodegenerative diseases (NDs), to fight ageing and nigrostriatal DAergic degeneration and promote functional recovery.

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PINK1 phosphorylates ubiquitin predominantly in astrocytes

Cited by 36 publications

References 49 publications

The Pathogenesis of Parkinson's Disease: A Complex Interplay Between Astrocytes, Microglia, and T Lymphocytes?

The Pathogenesis of Parkinson's Disease: A Complex Interplay Between Astrocytes, Microglia, and T Lymphocytes?

Molecular Mechanisms Underlying Synaptic and Axon Degeneration in Parkinson’s Disease

Nrf2/Wnt resilience orchestrates rejuvenation of glia-neuron dialogue in Parkinson's disease

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