Mutations in leucine-rich repeat kinase 2 (LRRK2) are a common cause of familial and sporadic Parkinson's disease (PD). Elevated LRRK2 kinase activity and neurodegeneration are linked, but the ...phosphosubstrate that connects LRRK2 kinase activity to neurodegeneration is not known. Here, we show that ribosomal protein s15 is a key pathogenic LRRK2 substrate in Drosophila and human neuron PD models. Phosphodeficient s15 carrying a threonine 136 to alanine substitution rescues dopamine neuron degeneration and age-related locomotor deficits in G2019S LRRK2 transgenic Drosophila and substantially reduces G2019S LRRK2-mediated neurite loss and cell death in human dopamine and cortical neurons. Remarkably, pathogenic LRRK2 stimulates both cap-dependent and cap-independent mRNA translation and induces a bulk increase in protein synthesis in Drosophila, which can be prevented by phosphodeficient T136A s15. These results reveal a novel mechanism of PD pathogenesis linked to elevated LRRK2 kinase activity and aberrant protein synthesis in vivo.
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.
Stroke is a major cause of mortality and morbidity worldwide. Extracellular glutamate accumulation leading to overstimulation of the ionotropic glutamate receptors mediates neuronal injury in stroke ...and in neurodegenerative disorders. Here we show that miR-223 controls the response to neuronal injury by regulating the functional expression of the glutamate receptor subunits GluR2 and NR2B in brain. Overexpression of miR-223 lowers the levels of GluR2 and NR2B by targeting 3′-UTR target sites (TSs) in GluR2 and NR2B, inhibits NMDA-induced calcium influx in hippocampal neurons, and protects the brain from neuronal cell death following transient global ischemia and excitotoxic injury. MiR-223 deficiency results in higher levels of NR2B and GluR2, enhanced NMDA-induced calcium influx, and increased miniature excitatory postsynaptic currents in hippocampal neurons. In addition, the absence of MiR-223 leads to contextual, but not cued memory deficits and increased neuronal cell death following transient global ischemia and excitotoxicity. These data identify miR-223 as a major regulator of the expression of GluR2 and NR2B, and suggest a therapeutic role for miR-223 in stroke and other excitotoxic neuronal disorders.
c-Abl is activated in the brain of Parkinson's disease (PD) patients and in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-intoxicated mice where it inhibits parkin through tyrosine ...phosphorylation leading to the accumulation of parkin substrates, and neuronal cell death. In the present study, we evaluated the in vivo efficacy of nilotinib, a brain penetrant c-Abl inhibitor, in the acute MPTP-induced model of PD. Our results show that administration of nilotinib reduces c-Abl activation and the levels of the parkin substrate, PARIS, resulting in prevention of dopamine (DA) neuron loss and behavioral deficits following MPTP intoxication. On the other hand, we observe no reduction in the tyrosine phosphorylation of parkin and the parkin substrate, AIMP2 suggesting that the protective effect of nilotinib may, in part, be parkin-independent or to the pharmacodynamics properties of nilotinib. This study provides a strong rationale for testing other brain permeable c-Abl inhibitors as potential therapeutic agents for the treatment of PD.
Poly(ADP-ribose) polymerase-1 (PARP-1) plays a pivotal role in multiple neurologic diseases by mediating caspase-independent cell death, which has recently been designated parthanatos to distinguish ...it from other forms of cell death such as apoptosis, necrosis and autophagy. Mitochondrial apoptosis-inducing factor (AIF) release and translocation to the nucleus is the commitment point for parthanatos. This process involves a pathogenic role of poly(ADP-ribose) (PAR) polymer. It generates in the nucleus and translocates to the mitochondria to mediate AIF release following lethal PARP-1 activation. PAR polymer itself is toxic to cells. Thus, PAR polymer signaling to mitochondrial AIF is the key event initiating the deadly crosstalk between the nucleus and the mitochondria in parthanatos. Targeting PAR-mediated AIF release could be a potential approach for the therapy of neurologic disorders.
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.
Analysis of human pathology led Braak to postulate that α-synuclein (α-syn) pathology could spread from the gut to brain via the vagus nerve. Here, we test this postulate by assessing ...α-synucleinopathy in the brain in a novel gut-to-brain α-syn transmission mouse model, where pathological α-syn preformed fibrils were injected into the duodenal and pyloric muscularis layer. Spread of pathologic α-syn in brain, as assessed by phosphorylation of serine 129 of α-syn, was observed first in the dorsal motor nucleus, then in caudal portions of the hindbrain, including the locus coeruleus, and much later in basolateral amygdala, dorsal raphe nucleus, and the substantia nigra pars compacta. Moreover, loss of dopaminergic neurons and motor and non-motor symptoms were observed in a similar temporal manner. Truncal vagotomy and α-syn deficiency prevented the gut-to-brain spread of α-synucleinopathy and associated neurodegeneration and behavioral deficits. This study supports the Braak hypothesis in the etiology of idiopathic Parkinson’s disease (PD).
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•Gut-to-brain propagation of pathologic α-synuclein via the vagus nerve causes PD•Dopamine neurons degenerate in the pathologic α-synuclein gut-to-brain model of PD•Gut injection of pathologic α-synuclein causes PD-like motor and non-motor symptoms•PD-like pathology and symptoms require endogenous α-synuclein
Gut injection of α-synuclein fibrils converts endogenous α-synuclein to a pathologic species that spreads to the brain. This leads to features of Parkinson’s disease, and vagotomy and α-synuclein deficiency prevent the neuropathology and neurobehavioral deficits induced by transmitted pathological α-synuclein.
Mitochondrial dynamics and mitophagy have been linked to cardiovascular and neurodegenerative diseases. Here, we demonstrate that the mitochondrial division dynamin Drp1 and the Parkinson's ...disease‐associated E3 ubiquitin ligase parkin synergistically maintain the integrity of mitochondrial structure and function in mouse heart and brain. Mice lacking cardiac Drp1 exhibited lethal heart defects. In Drp1KO cardiomyocytes, mitochondria increased their connectivity, accumulated ubiquitinated proteins, and decreased their respiration. In contrast to the current views of the role of parkin in ubiquitination of mitochondrial proteins, mitochondrial ubiquitination was independent of parkin in Drp1KO hearts, and simultaneous loss of Drp1 and parkin worsened cardiac defects. Drp1 and parkin also play synergistic roles in neuronal mitochondrial homeostasis and survival. Mitochondrial degradation was further decreased by combination of Drp1 and parkin deficiency, compared with their single loss. Thus, the physiological importance of parkin in mitochondrial homeostasis is revealed in the absence of mitochondrial division in mammals.
Synopsis
In vivo analysis reveals a synergistic role of mitochondrial fission protein Drp1 and Parkinson's disease‐associated ligase parkin in the regulation of ubiquitination and degradation of mitochondria in the heart and brain.
Mitochondria divide in cardiomyocytes.
Drp1 deficiency causes mitochondrial dysfunction, lethal heart failure and neurodegeneration due to defects in mitophagy.
Mitochondria enlarge and accumulate ubiquitinated outer membrane proteins and mitophagy adaptor protein p62 independently of parkin.
Parkin is dispensable for mitochondrial respiration, heart function and neuronal survival in the presence of Drp1‐regulated mitophagy.
Simultaneous loss of Drp1 and parkin increases mitophagy defects.
In vivo analysis reveals a synergistic role of mitochondrial fission protein Drp1 and Parkinson's disease‐associated ligase parkin in the regulation of ubiquitination and degradation of mitochondria in the heart and brain.
Parkin and PINK1: much more than mitophagy Scarffe, Leslie A; Stevens, Daniel A; Dawson, Valina L ...
Trends in neurosciences (Regular ed.),
06/2014, Letnik:
37, Številka:
6
Journal Article
Recenzirano
Odprti dostop
Highlights • Parkinson's disease is a mitochondrial disease of aging. • PINK1 and parkin are key players in multiple domains of mitochondrial health. • PINK1 and parkin are key regulators of ...mitochondrial quality control.
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