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.
Linked Articles
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
While glia are essential for regulating the homeostasis in the normal brain, their dysfunction contributes to neurodegeneration in many brain diseases, including Parkinson's disease (PD). Recent ...studies have identified that PD-associated genes are expressed in glial cells as well as neurons and have crucial roles in microglia and astrocytes. Here, we discuss the role of microglia and astrocytes dysfunction in relation to PD-linked mutations and their implications in PD pathogenesis. A better understanding of microglia and astrocyte functions in PD may provide insights into neurodegeneration and novel therapeutic approaches for PD.
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.
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.
Display omitted
Display omitted
► 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.
LRRK2 pathobiology in Parkinson's disease Martin, Ian; Kim, Jungwoo Wren; Dawson, Valina L. ...
Journal of neurochemistry,
December 2014, Letnik:
131, Številka:
5
Journal Article
Recenzirano
Odprti dostop
Mutations in the catalytic Roc‐COR and kinase domains of leucine‐rich repeat kinase 2 (LRRK2) are a common cause of familial Parkinson's disease (PD). LRRK2 mutations cause PD with age‐related ...penetrance and clinical features identical to late‐onset sporadic PD. Biochemical studies support an increase in LRRK2 kinase activity and a decrease in GTPase activity for kinase domain and Roc‐COR mutations, respectively. Strong evidence exists that LRRK2 toxicity is kinase dependent leading to extensive efforts to identify selective and brain‐permeable LRRK2 kinase inhibitors for clinical development. Cell and animal models of PD indicate that LRRK2 mutations affect vesicular trafficking, autophagy, protein synthesis, and cytoskeletal function. Although some of these biological functions are affected consistently by most disease‐linked mutations, others are not and it remains currently unclear how mutations that produce variable effects on LRRK2 biochemistry and function all commonly result in the degeneration and death of dopamine neurons. LRRK2 is typically present in Lewy bodies and its toxicity in mammalian models appears to be dependent on the presence of α‐synuclein, which is elevated in human iPS‐derived dopamine neurons from patients harboring LRRK2 mutations. Here, we summarize biochemical and functional studies of LRRK2 and its mutations and focus on aberrant vesicular trafficking and protein synthesis as two leading mechanisms underlying LRRK2‐linked disease.
LRRK2 mutations are a common cause of both familial and sporadic Parkinson's disease. Here, we review evidence describing the effects of these mutations on LRRK2 kinase and GTPase activities as a key driver of LRRK2 toxicity. We also discuss the reported impact of pathogenic mutations on cellular pathways which provide important clues on mechanisms of disease development.
LRRK2 mutations are a common cause of both familial and sporadic Parkinson's disease. Here, we review evidence describing the effects of these mutations on LRRK2 kinase and GTPase activities as a key driver of LRRK2 toxicity. We also discuss the reported impact of pathogenic mutations on cellular pathways which provide important clues on mechanisms of disease development.
Parkinson's disease (PD) is a neurodegenerative movement disorder characterized by the progressive loss of dopaminergic (DA) neurons. Most PD cases are sporadic; however, rare familial forms have ...been identified. Autosomal recessive PD (ARPD) results from mutations in Parkin, PINK1, DJ-1, and ATP13A2, while rare, atypical juvenile ARPD result from mutations in FBXO7, DNAJC6, SYNJ1, and PLA2G6. Studying these genes and their function has revealed mitochondrial quality control, protein degradation processes, and oxidative stress responses as common pathways underlying PD pathogenesis. Understanding how aberrancy in these common processes leads to neurodegeneration has provided the field with numerous targets that may be therapeutically relevant to the development of disease-modifying treatments.
PDF
