Abstract Parkinson's disease (PD) is the second most common neurodegenerative disease, after Alzheimer's disease. The potential causes of PD remain uncertain, but recent studies suggest ...neuroinflammation and microglia activation play important roles in PD pathogenesis. Major unanswered questions include whether protein aggregates cause the selective loss of dopaminergic neurons in the substantia nigra that underlies the clinical symptoms and whether neuroinflammation is a consequence or a cause of nigral cell loss. Within the microenvironment of the brain, glial cells play a critical role in homeostatic mechanisms that promote neuronal survival. Microglia have a specialized immune surveillance role and mediate innate immune responses to invading pathogens by secreting a myriad of factors that include, cytokines, chemokines, prostaglandins, reactive oxygen and nitrogen species, and growth factors. Some of these factors have neuroprotective and trophic activities and aid in brain repair processes; while others enhance oxidative stress and trigger apoptotic cascades in neurons. Therefore, pro- and anti-inflammatory responses must be in balance to prevent the potential detrimental effects of prolonged or unregulated inflammation-induced oxidative stress on vulnerable neuronal populations. In this review, we discuss potential triggers of neuroinflammation and review the strongest direct evidence that chronic neuroinflammation may have a more important role to play in PD versus other neurodegenerative diseases. Alternatively, we propose that genetic deficiency is not the only way to reduce protective factors in the brain which may function to keep microglial responses in check or regulate the sensitivity of DA neurons. If chronic inflammation can be shown to decrease the levels of neuroprotective factors in the midbrain, in essence genetic haploinsufficiency of protective factors such as Parkin or RGS10 may result from purely environmental triggers (aging, chronic systemic disease, etc.), increasing the vulnerability to inflammation-induced nigral DA neuron death and predisposing an individual to development of PD. Lastly, we review the latest epidemiological and experimental evidence supporting the potential use of anti-inflammatory and immunomodulatory drugs as neuroprotective agents to delay the progressive nigrostriatal degeneration that leads to motor dysfunction in PD.
Highlights • Mutations in PINK1 and Parkin are linked to Parkinson’s disease. • PINK1 and Parkin are believed to function in a common pathway in mitochondrial autophagy. • Additional potential ...functions of PINK1 and Parkin are reviewed.
BACKGROUNDThe presence and reactivation of chronic viral infections, such as EBV, CMV, and HIV, have been proposed as potential contributors to long COVID (LC), but studies in well-characterized ...postacute cohorts of individuals with COVID-19 over a longer time course consistent with current case definitions of LC are limited.METHODSIn a cohort of 280 adults with prior SARS-CoV-2 infection, we assessed the presence and types of LC symptoms and prior medical history (including COVID-19 history and HIV status) and performed serological testing for EBV and CMV using a commercial laboratory. We used covariate-adjusted binary logistic regression models to identify independent associations between variables and LC symptoms.RESULTSWe observed that LC symptoms, such as fatigue and neurocognitive dysfunction, at a median of 4 months following initial diagnosis were independently associated with serological evidence suggesting recent EBV reactivation (early antigen-diffuse IgG positivity) or high nuclear antigen (EBNA) IgG levels but not with ongoing EBV viremia. Serological evidence suggesting recent EBV reactivation (early antigen-diffuse IgG positivity) was most strongly associated with fatigue (OR = 2.12). Underlying HIV infection was also independently associated with neurocognitive LC (OR = 2.5). Interestingly, participants who had serologic evidence of prior CMV infection were less likely to develop neurocognitive LC (OR = 0.52).CONCLUSIONOverall, these findings suggest differential effects of chronic viral coinfections on the likelihood of developing LC and association with distinct syndromic patterns. Further assessment during the acute phase of COVID-19 is warranted.TRIAL REGISTRATIONLong-term Impact of Infection with Novel Coronavirus; ClinicalTrials.gov NCT04362150.FUNDINGThis work was supported by NIH/National Institute of Allergy and Infectious Diseases grants (3R01AI141003-03S1, R01AI158013, and K24AI145806); the Zuckerberg San Francisco General Hospital Department of Medicine and Division of HIV, Infectious Diseases, and Global Medicine; and the UCSF-Bay Area Center for AIDS Research (P30-AI027763).
Dominantly inherited mutations in the leucine-rich repeat kinase 2 gene (LRRK2) are the most common cause of familial Parkinson's disease (PD) and have also been identified in individuals with ...sporadic PD. Although the exact cellular function of LRRK2 remains unknown, most PD-linked mutations appear to be toxic to cells in culture via mechanisms that depend on the kinase activity of LRRK2 or on the formation of cytoplasmic inclusions. Here we show that the E3 ubiquitin ligase CHIP physically associates with LRRK2 and regulates the cellular abundance of LRRK2. We further show that LRRK2 forms a complex with overexpressed and endogenous CHIP and Hsp90. Our data indicates that the destabilization of LRRK2 by CHIP is due to ubiquitination and proteasome-dependent degradation. Hsp90 can attenuate CHIP-mediated degradation and this can be blocked by the Hsp90 inhibitor geldanamycin. These findings provide important insight into the cellular regulation of LRRK2 stability and may lead to the development of therapeutics to treat PD based on controlling LRRK2 stability.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Catecholamine-induced lipolysis, the first step in the generation of energy substrates by the hydrolysis of triglycerides, declines with age. The defect in the mobilization of free fatty acids in the ...elderly is accompanied by increased visceral adiposity, lower exercise capacity, failure to maintain core body temperature during cold stress, and reduced ability to survive starvation. Although catecholamine signalling in adipocytes is normal in the elderly, how lipolysis is impaired in ageing remains unknown. Here we show that adipose tissue macrophages regulate the age-related reduction in adipocyte lipolysis in mice by lowering the bioavailability of noradrenaline. Unexpectedly, unbiased whole-transcriptome analyses of adipose macrophages revealed that ageing upregulates genes that control catecholamine degradation in an NLRP3 inflammasome-dependent manner. Deletion of NLRP3 in ageing restored catecholamine-induced lipolysis by downregulating growth differentiation factor-3 (GDF3) and monoamine oxidase A (MAOA) that is known to degrade noradrenaline. Consistent with this, deletion of GDF3 in inflammasome-activated macrophages improved lipolysis by decreasing levels of MAOA and caspase-1. Furthermore, inhibition of MAOA reversed the age-related reduction in noradrenaline concentration in adipose tissue, and restored lipolysis with increased levels of the key lipolytic enzymes adipose triglyceride lipase (ATGL) and hormone sensitive lipase (HSL). Our study reveals that targeting neuro-immunometabolic signalling between the sympathetic nervous system and macrophages may offer new approaches to mitigate chronic inflammation-induced metabolic impairment and functional decline.
•α-Synuclein aggregates appear as early as two weeks after injection of α-synuclein pre-formed fibrils into rat striatum.•PD-linked PINK1-deficiency causes greater pS129 α-synuclein pathology in rats ...injected with α-synuclein pre-formed fibrils.•PINK1 KO rats are more susceptible to nigral cell loss induced by intracranial injection of α-synuclein pre-formed fibrils.
The main neuropathological hallmarks of Parkinson’s disease (PD) are loss of dopaminergic neurons in the substantia nigra and intraneuronal protein aggregates immunoreactive for α-synuclein phosphorylated at serine 129 (pS129). Most cases of PD are idiopathic; however, genetic mutations have been identified in several genes linked to familial PD. Mutations in the gene encoding α-synuclein are causally linked to dominantly inherited forms of PD and mutations in the PTEN-induced kinase-1 (PINK1) gene are linked to recessively inherited forms of PD. Because abnormal α-synuclein protein aggregates appear spontaneously in PINK1 knockout (KO) rats, we hypothesize that PINK1-deficiency causes endogenous α-synuclein to be more prone to aggregation. α-Synuclein aggregation does not normally occur in mice or rats, however, it can be induced by intracranial injection of α-synuclein pre-formed fibrils (PFFs), which also induces loss of dopaminergic nigral neurons 3–6 months post-injection. Because PINK1-deficiency is linked to early-onset PD, we further hypothesize that PINK1 KO rats will show earlier PFF-induced neurodegeneration compared to wild-type (WT) rats. Herein, we report that intracranial injection of α-synuclein PFFs into the dorsal striatum induced more abundant pS129 α-synuclein in PINK1 KO rat brains compared to WT littermate controls. Moreover, the synuclein extracted from the brains of PFF-injected PINK1 KO rats was more insoluble compared to PFF-injected WT littermates, suggesting greater progression of α-synuclein pathology in PINK1 KO rats. Four weeks post-injection, PFFs caused significant loss of dopaminergic neurons in the substantia nigra of PINK1 KO rats, but not WT controls. Together, our results indicate that PINK1 deficiency increases vulnerability to α-synuclein aggregation and dopaminergic neurodegeneration in vivo.
Parkinson’s disease (PD) is the most common neurodegenerative movement disorder. There are no available therapeutics that slow or halt the progressive loss of dopamine-producing neurons, which ...underlies the primary clinical symptoms. Currently approved PD drugs can provide symptomatic relief by increasing brain dopamine content or activity; however, the alleviation is temporary, and the effectiveness diminishes with the inevitable progression of neurodegeneration. Discovery and development of disease-modifying neuroprotective therapies has been hampered by insufficient understanding of the root cause of PD-related neurodegeneration. The etiology of PD involves a combination of genetic and environmental factors. Although a single cause has yet to emerge, genetic, cell biological and neuropathological evidence implicates mitochondrial dysfunction and protein aggregation. Postmortem PD brains show pathognomonic Lewy body intraneuronal inclusions composed of aggregated α-synuclein, indicative of failure to degrade misfolded protein. Mutations in the genes that code for α-synuclein, as well as the E3 ubiquitin ligase Parkin, cause rare inherited forms of PD. While many ubiquitin ligases label proteins with ubiquitin chains to mark proteins for degradation by the proteasome, Parkin has been shown to mark dysfunctional mitochondria for degradation by mitophagy. The ubiquitin proteasome system participates in several aspects of the cell’s response to mitochondrial damage, affording numerous therapeutic opportunities to augment mitophagy and potentially stop PD progression. This review examines the role and therapeutic potential of such UPS modulators, exemplified by both ubiquitinating and deubiquitinating enzymes.
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