Ferroptosis and cell death mechanisms in Parkinson's disease
Introduction
Parkinson's disease (PD) is typified by death of neurons in the substantia nigra pars compacta (SNpc), which is a region of the basal ganglia that regulates execution and control of motor function, cause rigidity, tremor and other motor symptoms that typify the disease (Fearnley and Lees, 1991, Rinne et al., 1989b). While other regions of pronounced cell loss include the locus coeruleus (Zarow et al., 2003) and nucleus basalis of Meynert (Nakano and Hirano, 1984), there is a strong correlation between the loss of nigral dopaminergic neurons and motor impairment in PD patients (Rinne et al., 1989a, Rinne et al., 1989b). Treatment with levodopa elevates striatal dopamine levels that are depleted by SNpc neurodegeneration in PD, however levodopa and other dopamine-based therapies only partially relieve motor symptoms during the early stages of the disease and have no effect on disease progression (Ahlskog and Muenter, 2001, Marsden and Parkes, 1977, Miyawaki et al., 1997). Unfortunately no disease-modifying therapies for PD have yet been identified, and the search for a drug that slows or prevents the death of neurons in the PD brain is a priority. While there are many pathogenic factors implicated in PD, including the protein alpha-synuclein (αsyn) (Baba et al., 1998, Edwards et al., 2010, Pankratz et al., 2009, Satake et al., 2009, Simon-Sanchez et al., 2009, Spillantini et al., 1997), it is currently unknown how these cause or contribute to neuronal death.
Multiple genetic loci and mutations have been identified as disease-causative or risk factors for idiopathic or familial PD, however, several genetic studies, including multiple genome-wide association studies (GWAS), have identified SNCA, the αsyn-encoding gene, as one of the strongest independent genetic risk loci for developing idiopathic and familial forms of PD (Edwards et al., 2010, Pankratz et al., 2009, Satake et al., 2009, Simon-Sanchez et al., 2009). Affected members of families identified with the SNCA point mutations A53T (Polymeropoulos et al., 1997), A30P (Kruger et al., 1998), E46K (Zarranz et al., 2004), H50Q (Appel-Cresswell et al., 2013, Proukakis et al., 2013), and G51D (Lesage et al., 2013) exhibit early-onset PD. Duplication (Ikeuchi et al., 2008, Obi et al., 2008) and triplication (Fuchs et al., 2007, Singleton et al., 2003) of the SNCA locus also causes familial PD, which further implicates αsyn as an important mediator of Parkinsonian neurodegeneration.
Intraneuronal Lewy bodies (LB), of which insoluble αsyn fibrils are the major protein component (Baba et al., 1998, Spillantini et al., 1997), are a pathological feature of the SN in the majority of PD cases (Gibb and Lees, 1988, Hughes et al., 1992, Spillantini et al., 1997). The formation of these fibrils follows the conversion of monomeric to oligomeric αsyn (Baba et al., 1998, Giasson et al., 2001), which has been identified as a neurotoxic species in vivo (Winner et al., 2011). Striatal injection of exogenously aggregated αsyn into non-transgenic mice induced LB-like deposits and loss of dopaminergic neurons in the SN and Parkinsonian behavioural deficits (Luk et al., 2012). Multiple studies involving different injection sites have since demonstrated that aggregated αsyn is inherently pathogenic (Masuda-Suzukake et al., 2013, Sacino et al., 2014), which supports the hypothesis that αsyn pathology spreads around the brain in stages that correlate with symptom development in patients (Braak et al., 2003, Braak et al., 2004). Therefore, it appears that there is a causal link between αsyn and Parkinsonian neurodegeneration. However, the mechanisms underlying how this protein causes cell death in PD are undefined, and the identification of these cellular processes could lead to a novel therapeutic target to slow PD progression.
Section snippets
Cell death mechanisms of Parkinsonian neurodegeneration
There are multiple cell death mechanisms implicated in PD pathogenesis, and a newly identified pathway referred to as ferroptosis has also recently been linked to PD (Do Van et al., 2016). Ferroptosis is an iron-dependent cell death pathway that involves depletion of intracellular reduced-glutathione (GSH) levels (Bannai, 1986, Yang et al., 2014) (the major antioxidant of neurons and natural ligand for iron in the ‘labile iron pool’ (LIP)) (Hider and Kong, 2011), and lipid peroxidation (Yang
Conclusion
This review has described the currently recognised neuronal cell death pathways, and their potential links to PD. Multiple pathways are likely to be involved in Parkinsonian neurodegeneration; the pathways that have the most support as candidates for PD-specific cell death appear to be intrinsic and extrinsic caspase-dependent apoptosis, and autophagic cell death, which have been studied extensively for several decades in regards to PD. Ferroptosis is a new cell death pathway that has only
Conflicts of interest
The authors declare no conflicts of interest.
Acknowledgements
Supported by an Australian Government Research Training Program Scholarship, funds from the Australian National Health & Medical Research Council (NHMRC) and Operational Infrastructure Support from the Victorian State Government.
References (241)
Exchange of cystine and glutamate across plasma membrane of human fibroblasts
J. Biol. Chem.
(1986)- et al.
Is hydroxyl radical generated by the Fenton reaction in vivo?
Biochem. Biophys. Res. Commun.
(1985) - et al.
p53 and Bax activation in 6-hydroxydopamine-induced apoptosis in PC12 cells
Brain Res.
(1997) - et al.
Staging of brain pathology related to sporadic Parkinson's disease
Neurobiol. Aging
(2003) - et al.
The accumulation of neurotoxic proteins, induced by proteasome inhibition, is reverted by trehalose, an enhancer of autophagy, in human neuroblastoma cells
Neurochem. Int.
(2011) - et al.
Elevated reactive oxygen species and antioxidant enzyme activities in animal and cellular models of Parkinson's disease
Biochim. Biophys. Acta
(1997) - et al.
Mitochondrial alpha-synuclein accumulation impairs complex I function in dopaminergic neurons and results in increased mitophagy in vivo
Neurosci. Lett.
(2010) - et al.
Alterations in lysosomal and proteasomal markers in Parkinson's disease: relationship to alpha-synuclein inclusions
Neurobiol. Dis.
(2009) - et al.
Poly(ADP-ribose) polymerase inhibitors protect against MPTP-induced depletions of striatal dopamine and cortical noradrenaline in C57B1/6 mice
Brain Res.
(1996) - et al.
Curcumin protects against iron induced neurotoxicity in primary cortical neurons by attenuating necroptosis
Neurosci. Lett.
(2013)
Lipid peroxidation as cause of nigral cell death in Parkinson's disease
Lancet
Ferroptosis: an iron-dependent form of nonapoptotic cell death
Cell
Ferroptosis, a newly characterized form of cell death in Parkinson's disease that is regulated by PKC
Neurobiol. Dis.
The iron exporter ferroportin/Slc40a1 is essential for iron homeostasis
Cell Metab.
Iron-export ferroxidase activity of β-amyloid precursor protein is inhibited by zinc in Alzheimer's disease
Cell
Progressive neurodegeneration and motor disabilities induced by chronic expression of IL-1beta in the substantia nigra
Neurobiol. Dis.
Cellular euthanasia mediated by a nuclear enzyme: a central role for nuclear ADP-ribosylation in cellular metabolism
Trends Biochem. Sci.
A hydrophobic stretch of 12 amino acid residues in the middle of alpha-synuclein is essential for filament assembly
J. Biol. Chem.
Cell death by necrosis: towards a molecular definition
Trends Biochem. Sci.
Magnesium inhibits spontaneous and iron-induced aggregation of alpha-synuclein
J. Biol. Chem.
Neuromelanin-containing neurons of the substantia nigra accumulate iron and aluminum in Parkinson's disease: a LAMMA study
Brain Res.
Clinical perspectives of PARP inhibitors
Pharmacol. Res.
ATP13A2 regulates mitochondrial bioenergetics through macroautophagy
Neurobiol. Dis.
Further evidence for an association between a mutation in the APP gene and Lewy body formation
Neurosci. Lett.
6-Hydroxydopamine induced apoptosis of dopaminergic cells in the rat substantia nigra
Brain Res.
Frequency of levodopa-related dyskinesias and motor fluctuations as estimated from the cumulative literature
Mov. Disord. Official J. Mov. Disord. Soc.
Neuroprotection by BDNF against glutamate-induced apoptotic cell death is mediated by ERK and PI3-kinase pathways
Cell Death Differ.
The PARP superfamily
BioEssays News Rev. Mol. Cell. Dev. Biol.
Apoptosis and autophagy in nigral neurons of patients with Parkinson's disease
Histol. Histopathol.
Matrix attachment regulates Fas-induced apoptosis in endothelial cells: a role for c-flip and implications for anoikis
J. Cell Biol.
Alpha-synuclein p.H50Q, a novel pathogenic mutation for Parkinson's disease
Mov. Disord. Official J. Mov. Disord. Soc.
Parkinson's Disease Iron Deposition Caused by Nitric Oxide-induced Loss of APP
Ferritin levels in the cerebrospinal fluid predict Alzheimer's disease outcomes and are regulated by APOE
Nat. Commun.
Nigral iron elevation is an invariable feature of Parkinson's disease and is a sufficient cause of neurodegeneration
Biomed. Res. Int.
Iron accumulation confers neurotoxicity to a vulnerable population of nigral neurons: implications for Parkinson's disease
Mol. Neurodegener.
Ceruloplasmin dysfunction and therapeutic potential for Parkinson disease
Ann. Neurol.
Parkinson's disease iron deposition caused by nitric oxide-induced loss of beta-amyloid precursor protein
J. Neurosci. Official J. Soc. Neurosci.
Aggregation of alpha-synuclein in Lewy bodies of sporadic Parkinson's disease and dementia with Lewy bodies
Am. J. Pathol.
Glial pathology but absence of apoptotic nigral neurons in long-standing Parkinson's disease
Mov. Disord. Official J. Mov. Disord. Soc.
Increased basal ganglia iron levels in Huntington disease
Arch. Neurol.
Excitotoxicity and nitric oxide in Parkinson's disease pathogenesis
Ann. Neurol.
Alpha-synuclein alters toll-like receptor expression
Front. Neurosci.
Interleukin-1 beta and interleukin-6 are elevated in the cerebrospinal fluid of Alzheimer's and de novo Parkinson's disease patients
Neurosci. Lett.
Autophagy induction and autophagosome clearance in neurons: relationship to autophagic pathology in Alzheimer's disease
J. Neurosci. Official J. Soc. Neurosci.
Association study between iron-related genes polymorphisms and Parkinson's disease
J. Neurol.
BAX channel activity mediates lysosomal disruption linked to Parkinson disease
Autophagy
Stages in the development of Parkinson's disease-related pathology
Cell Tissue Res.
Glitazone treatment and incidence of Parkinson's disease among people with diabetes: a retrospective cohort study
PLoS Med.
Salmonella induces macrophage death by caspase-1-dependent necrosis
Mol. Microbiol.
Cell-autonomous Fas (CD95)/Fas-ligand interaction mediates activation-induced apoptosis in T-cell hybridomas
Nature
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