That certain cell types in the central nervous system are more likely to undergo neurodegeneration in Parkinson's disease is a widely appreciated but poorly understood phenomenon. Many vulnerable ...subpopulations, including dopamine neurons in the substantia nigra pars compacta, have a shared phenotype of large, widely distributed axonal networks, dense synaptic connections, and high basal levels of neural activity. These features come at substantial bioenergetic cost, suggesting that these neurons experience a high degree of mitochondrial stress. In such a context, mechanisms of mitochondrial quality control play an especially important role in maintaining neuronal survival. In this review, we focus on understanding the unique challenges faced by the mitochondria in neurons vulnerable to neurodegeneration in Parkinson's and summarize evidence that mitochondrial dysfunction contributes to disease pathogenesis and to cell death in these subpopulations. We then review mechanisms of mitochondrial quality control mediated by activation of PINK1 and Parkin, two genes that carry mutations associated with autosomal recessive Parkinson's disease. We conclude by pinpointing critical gaps in our knowledge of PINK1 and Parkin function, and propose that understanding the connection between the mechanisms of sporadic Parkinson's and defects in mitochondrial quality control will lead us to greater insights into the question of selective vulnerability.
Cells die by a variety of mechanisms. Terminally differentiated cells such as neurones die in a variety of disorders, in part, via parthanatos, a process dependent on the activity of poly ...(ADP‐ribose)‐polymerase (PARP). Parthanatos does not require the mediation of caspases for its execution, but is clearly mechanistically dependent on the nuclear translocation of the mitochondrial‐associated apoptosis‐inducing factor (AIF). The nuclear translocation of this otherwise beneficial mitochondrial protein, occasioned by poly (ADP‐ribose) (PAR) produced through PARP overactivation, causes large‐scale DNA fragmentation and chromatin condensation, leading to cell death. This review describes the multistep course of parthanatos and its dependence on PAR signalling and nuclear AIF translocation. The review also discusses potential targets in the parthanatos cascade as promising avenues for the development of novel, disease‐modifying, therapeutic agents.
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This article is part of a themed issue on Mitochondrial Pharmacology: Energy, Injury & Beyond. To view the other articles in this issue visit http://dx.doi.org/10.1111/bph.2014.171.issue‐8
The cell biology of Parkinson's disease Panicker, Nikhil; Ge, Preston; Dawson, Valina L ...
The Journal of cell biology,
04/2021, Letnik:
220, Številka:
4
Journal Article
Recenzirano
Odprti dostop
Parkinson's disease (PD) is a progressive neurodegenerative disorder resulting from the death of dopamine neurons in the substantia nigra pars compacta. Our understanding of PD biology has been ...enriched by the identification of genes involved in its rare, inheritable forms, termed PARK genes. These genes encode proteins including α-syn, LRRK2, VPS35, parkin, PINK1, and DJ1, which can cause monogenetic PD when mutated. Investigating the cellular functions of these proteins has been instrumental in identifying signaling pathways that mediate pathology in PD and neuroprotective mechanisms active during homeostatic and pathological conditions. It is now evident that many PD-associated proteins perform multiple functions in PD-associated signaling pathways in neurons. Furthermore, several PARK proteins contribute to non-cell-autonomous mechanisms of neuron death, such as neuroinflammation. A comprehensive understanding of cell-autonomous and non-cell-autonomous pathways involved in PD is essential for developing therapeutics that may slow or halt its progression.
The COVID-19 pandemic has profoundly altered the daily lives of many people across the globe, both through the direct interpersonal cost of the disease, and the governmental restrictions imposed to ...mitigate its spread and impact. The UK has been particularly affected and has one of the highest mortality rates in Europe. In this paper, we examine the impact of COVID-19 on psychological health and well-being in the UK during a period of ‘lockdown’ (15th–21st May 2020) and the specific role of Psychological Flexibility as a potential mitigating process.
We observed clinically high levels of distress in our sample (N = 555). However, psychological flexibility was significantly and positively associated with greater wellbeing, and inversely related to anxiety, depression, and COVID-19-related distress. Avoidant coping behaviour was positively associated with all indices of distress and negatively associated with wellbeing, while engagement in approach coping only demonstrated weaker associations with outcomes of interest. No relationship between adherence to government guidelines and psychological flexibility was found.
In planned regression models, psychological flexibility demonstrated incremental predictive validity for all distress and wellbeing outcomes (over and above both demographic characteristics and COVID-19-specific coping responses). Furthermore, psychological flexibility and COVID-19 outcomes were only part-mediated by coping responses to COVID-19, supporting the position that psychological flexibility can be understood as an overarching response style that is distinct from established conceptualisations of coping. We conclude that psychological flexibility represents a promising candidate process for understanding and predicting how an individual may be affected by, and cope with, both the acute and longer-term challenges of the pandemic.
•Our UK population sample report high levels of COVID-19 distress.•Psychological flexibility likely accounts for variance in wellbeing and distress.•Adherent social distancing was not related to psychological flexibility.•Psychological flexibility disposes adaptive COVID-19 coping responses.•Coping responses may part-mediate associations with psychological flexibility.
A hallmark of Parkinson's disease (PD) is the preferential loss of substantia nigra dopamine neurons. Here, we identify a new
parkin
interacting
substrate, PARIS (ZNF746), whose levels are regulated ...by the ubiquitin proteasome system via binding to and ubiquitination by the E3 ubiquitin ligase, parkin. PARIS is a KRAB and zinc finger protein that accumulates in models of parkin inactivation and in human PD brain. PARIS represses the expression of the transcriptional coactivator, PGC-1α and the PGC-1α target gene, NRF-1 by binding to insulin response sequences in the PGC-1α promoter. Conditional knockout of parkin in adult animals leads to progressive loss of dopamine (DA) neurons in a PARIS-dependent manner. Moreover, overexpression of PARIS leads to the selective loss of DA neurons in the substantia nigra, and this is reversed by either parkin or PGC-1α coexpression. The identification of PARIS provides a molecular mechanism for neurodegeneration due to parkin inactivation.
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► PARIS (ZNF746) is a substrate of the E3 ubiquitin ligase parkin ► PARIS accumulates in parkin inactivation models and in human Parkinson's disease brain ► PARIS transcriptionally represses PGC-1α by binding to insulin responsive sequences ► Degeneration of dopamine neurons in conditional parkin knockouts depends on PARIS
Parkinson's disease (PD) is a progressive neurodegenerative disorder that is characterized by the degeneration of dopamine (DA) and non-DA neurons, the almost uniform presence of Lewy bodies, and ...motor deficits. Although the majority of PD is sporadic, specific genetic defects in rare familial cases have provided unique insights into the pathogenesis of PD. Through the creation of animal and cellular models of mutations in LRRK2 and α-synuclein, which are linked to autosomal-dominant PD, and mutations in parkin, DJ-1, and PINK1, which are responsible for autosomal-recessive PD, insight into the molecular mechanisms of this disorder are leading to new ideas about the pathogenesis of PD. In this review, we discuss the animal models for these genetic causes of PD, their limitations, and value. Moreover, we discuss future directions and potential strategies for optimization of the genetic models.
Parkinson's disease (PD) is a complex disorder with many different causes, yet they may intersect in common pathways, raising the possibility that neuroprotective agents may have broad applicability ...in the treatment of PD. Current evidence suggests that mitochondrial complex I inhibition may be the central cause of sporadic PD and that derangements in complex I cause α-synuclein aggregation, which contributes to the demise of dopamine neurons. Accumulation and aggregation of α-synuclein may further contribute to the death of dopamine neurons through impairments in protein handling and detoxification. Dysfunction of parkin (a ubiquitin E3 ligase) and DJ-1 could contribute to these deficits. Strategies aimed at restoring complex I activity, reducing oxidative stress and α-synuclein aggregation, and enhancing protein degradation may hold particular promise as powerful neuroprotective agents in the treatment of PD.
Genetic studies have provided valuable insight into the pathological mechanisms underlying Parkinson's disease (PD). The elucidation of genetic components to what was once largely considered a ...nongenetic disease has given rise to a multitude of cell and animal models enabling the dissection of molecular pathways involved in disease etiology. Here, we review advances obtained from models of dominant mutations in α-synuclein and LRRK2 as well as recessive PINK1, parkin and DJ-1 mutations. Recent genome-wide association studies have implicated genetic variability at two of these loci, α-synuclein and LRRK2, as significant risk factors for developing sporadic PD. This, coupled with the established role of mitochondrial impairment in both familial and sporadic PD, highlights the likelihood of common mechanisms fundamental to the etiology of both.
In 2009, the Nomenclature Committee on Cell Death (NCCD) proposed a set of recommendations for the definition of distinct cell death morphologies and for the appropriate use of cell death-related ...terminology, including 'apoptosis', 'necrosis' and 'mitotic catastrophe'. In view of the substantial progress in the biochemical and genetic exploration of cell death, time has come to switch from morphological to molecular definitions of cell death modalities. Here we propose a functional classification of cell death subroutines that applies to both in vitro and in vivo settings and includes extrinsic apoptosis, caspase-dependent or -independent intrinsic apoptosis, regulated necrosis, autophagic cell death and mitotic catastrophe. Moreover, we discuss the utility of expressions indicating additional cell death modalities. On the basis of the new, revised NCCD classification, cell death subroutines are defined by a series of precise, measurable biochemical features.
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