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1.  Enhancing nucleotide metabolism protects against mitochondrial dysfunction and neurodegeneration in a PINK1 model of Parkinson’s disease 
Nature cell biology  2014;16(2):157-166.
Mutations in PINK1 cause early-onset Parkinson’s disease (PD). Studies in Drosophila melanogaster have highlighted mitochondrial dysfunction on loss of Pink1 as a central mechanism of PD pathogenesis. Here we show that global analysis of transcriptional changes in Drosophila pink1 mutants reveals an upregulation of genes involved in nucleotide metabolism, critical for neuronal mitochondrial DNA synthesis. These key transcriptional changes were also detected in brains of PD patients harbouring PINK1 mutations. We demonstrate that genetic enhancement of the nucleotide salvage pathway in neurons of pink1 mutant flies rescues mitochondrial impairment. In addition, pharmacological approaches enhancing nucleotide pools reduce mitochondrial dysfunction caused by Pink1 deficiency. We conclude that loss of Pink1 evokes the activation of a previously unidentified metabolic reprogramming pathway to increase nucleotide pools and promote mitochondrial biogenesis. We propose that targeting strategies enhancing nucleotide synthesis pathways may reverse mitochondrial dysfunction and rescue neurodegeneration in PD and, potentially, other diseases linked to mitochondrial impairment.
PMCID: PMC4199097  PMID: 24441527
2.  Prions: Generation and Spread Versus Neurotoxicity 
The Journal of Biological Chemistry  2014;289(29):19862-19868.
Neurodegenerative diseases are characterized by the aggregation of misfolded proteins in the brain. Among these disorders are the prion diseases, which are transmissible, and in which the misfolded proteins (“prions”) are also the infectious agent. Increasingly, it appears that misfolded proteins in Alzheimer and Parkinson diseases and the tauopathies also propagate in a “prion-like” manner. However, the association between prion formation, spread, and neurotoxicity is not clear. Recently, we showed that in prion disease, protein misfolding leads to neurodegeneration through dysregulation of generic proteostatic mechanisms, specifically, the unfolded protein response. Genetic and pharmacological manipulation of the unfolded protein response was neuroprotective despite continuing prion replication, hence dissociating this from neurotoxicity. The data have clear implications for treatment across the spectrum of these disorders, targeting pathogenic processes downstream of protein misfolding.
PMCID: PMC4106307  PMID: 24860100
Alzheimer Disease; Gene Therapy; Neurodegeneration; Prion; Unfolded Protein Response (UPR); Alzheimer's; Neuroprotection
3.  miRNAs-19b, -29b-2* and -339-5p Show an Early and Sustained Up-Regulation in Ischemic Models of Stroke 
PLoS ONE  2013;8(12):e83717.
Stroke, the loss of neurons after ischemic insult to the brain, is one of the leading causes of death and disability worldwide. Despite its prevalence and severity, current therapy is extremely limited, highlighting the importance of further understanding the molecular events underlying ischemia-induced neuronal cell death. An ischemic area can be subdivided into two separate pathophysiological regions: the rapidly dying necrotic core, and the potentially salvageable apoptotic penumbra. Understanding molecular events occurring in the apoptotic ischemic penumbra may give greater insight into mechanisms controlling this salvageable tissue. miRNAs are known to have key roles in the regulation of gene expression in numerous pathological conditions, including the modulation of distinct pathways in stroke. However, previous studies have profiled miRNAs in the whole ischemic infarct, and do not differentiate between miRNA regulation in the necrotic core versus the apoptotic penumbra. We asked if there were unique miRNAs that are differentially regulated following ischemic insults in the salvageable apoptotic penumbra. miRNA expression profiles were compared in the whole infarct from in vivo stroke models, using the three vessel occlusion approach, to an in vitro model of the ischemic penumbra, prior to apoptotic induction. Multiple miRNAs were found to be differentially regulated following ischemic insults in each system. However, miR-19b, miR-29b-2* and miR-339-5p were significantly up-regulated in both model systems. Further, we confirmed these results in a neuroblastoma cell line subjected to a penumbra-like ischemic insult that induced the apoptotic cell death pathway. The data show that miR-19b, miR-29b-2* and miR-339-5p are up-regulated following ischemic insults and may be regulating gene expression to control important cellular pathways in the salvageable ischemic penumbra. Further investigation of their role and mRNA target identification may lead to new insights into the molecular mechanisms taking place in the salvageable apoptotic penumbra.
PMCID: PMC3869799  PMID: 24376737
4.  Sustained translational repression by eIF2α–P mediates prion neurodegeneration 
Nature  2012;485(7399):507-511.
The mechanisms leading to neuronal death in neurodegenerative disease are poorly understood. Many of these disorders, including Alzheimer’s (AD), Parkinson’s (PD) and prion diseases, are associated with the accumulation of misfolded disease-specific proteins. The unfolded protein response (UPR) is a protective cellular mechanism triggered by rising levels of misfolded proteins. One arm of this pathway results in the transient shutdown of protein translation, through phosphorylation of the alpha subunit of eukaryotic translation initiation factor, eIF2α. UPR activation and/or increased eIF2α–P levels are seen in patients with AD, PD and prion disease 1-4, but how this links to neurodegeneration is unknown. Here we show that accumulation of prion protein (PrP) during prion replication causes persistent translational repression of global protein synthesis by eIF2α–P, associated with synaptic failure and neuronal loss in prion-diseased mice. Further, we show that promoting translational recovery in hippocampi of prion-infected mice is neuroprotective. Over-expression of GADD34, a specific eIF2α–P phosphatase, as well as reduction of PrP levels by lentivirally-mediated RNAi, reduced eIF2α–P levels. As a result, both approaches restored vital translation rates during prion disease, rescuing synaptic deficits and neuronal loss, and thereby significantly increasing survival. In contrast, salubrinal, an inhibitor of eIF2α-P dephosphorylation5 increased eIF2α-P levels, exacerbating neurotoxicity and significantly reducing survival in prion diseased mice. Given the prevalence of protein misfolding and UPR activation in several neurodegenerative diseases, our results suggest that manipulation of common pathways such as translational control, rather than disease-specific approaches, may lead to new therapies preventing synaptic failure and neuronal loss across the spectrum of these disorders.
PMCID: PMC3378208  PMID: 22622579
5.  Prion neurodegeneration 
Prion  2009;3(4):195-201.
Synaptic dysfunction is a key process in the evolution of many neurodegenerative diseases, with synaptic loss preceding that of neuronal cell bodies. In Alzheimer, Huntington, and prion diseases early synaptic changes correlate with cognitive and motor decline, and altered synaptic function may also underlie deficits in a number of psychiatric and neurodevelopmental conditions. The formation, remodelling and elimination of spines and synapses are continual physiological processes, moulding cortical architecture, underpinning the abilities to learn and remember. In disease, however, particularly in protein misfolding neurodegenerative disorders, lost synapses are not replaced and this loss is followed by neuronal death. These two processes are separately regulated, with mechanistic, spatial and temporal segregation of the death ‘routines’ of synapses and cell bodies. Recent insights into the reversibility of synaptic dysfunction in a mouse model of prion disease at neurophysiological, behavioral and morphological levels call for a deeper analysis of the mechanisms underlying neurotoxicity at the synapse, and have important implications for therapy of prion and other neurodegenerative disorders.
PMCID: PMC2807691  PMID: 19887910
neurodegeneration; prion; synaptic dysfunction; behavior; neurophysiology
6.  Therapy for prion diseases 
Prion  2009;3(3):121-128.
Insights into the molecular basis and the temporal evolution of neurotoxicity in prion disease are increasing, and recent work in mice leads to new avenues for targeting treatment of these disorders. Using lentivirally mediated RNA interference (RNAi) against native prion protein (PrP), White et al. report the first therapeutic intervention that results in neuronal rescue, prevents symptoms and increases survival in mice with established prion disease.1 Both the target and the timing of treatment here are crucial to the effectiveness of this strategy: the formation of the neurotoxic prion agent is prevented at a point when diseased neurons can still be saved from death. But the data also give new insights into the timing of treatment in the context of the pattern of spread of prion infection throughout the brain, with implications for developing the most effective treatments.
PMCID: PMC2802775  PMID: 19597349
prion; RNA interference; gene therapy; neurodegeneration; synaptic
7.  Nerve injury induces robust allodynia and ectopic discharges in Nav1.3 null mutant mice 
Molecular Pain  2006;2:33.
Changes in sodium channel activity and neuronal hyperexcitability contribute to neuropathic pain, a major clinical problem. There is strong evidence that the re-expression of the embryonic voltage-gated sodium channel subunit Nav1.3 underlies neuronal hyperexcitability and neuropathic pain.
Here we show that acute and inflammatory pain behaviour is unchanged in global Nav1.3 mutant mice. Surprisingly, neuropathic pain also developed normally in the Nav1.3 mutant mouse. To rule out any genetic compensation mechanisms that may have masked the phenotype, we investigated neuropathic pain in two conditional Nav1.3 mutant mouse lines. We used Nav1.8-Cre mice to delete Nav1.3 in nociceptors at E14 and NFH-Cre mice to delete Nav1.3 throughout the nervous system postnatally. Again normal levels of neuropathic pain developed after nerve injury in both lines. Furthermore, ectopic discharges from damaged nerves were unaffected by the absence of Nav1.3 in global knock-out mice. Our data demonstrate that Nav1.3 is neither necessary nor sufficient for the development of nerve-injury related pain.
PMCID: PMC1630424  PMID: 17052333

Results 1-7 (7)