A BACwards glance at neurodegeneration: molecular insights into disease from LRRK2, SNCA and MAPT BAC-transgenic mice. by Johnson, S, Wade-Martins, R

Molecular mechanisms underlying haplotypespecific regulation of gene expression at the microtubule associated protein tau locus by Lai, MC

Subjects: “…molecular neurodegeneration…”

Investigating the function of microtubule-associated protein tau (MAPT) and its genetic association with Parkinson’s using human iPSC-derived dopamine neurons by Beevers, J

Subjects: “…Neurodegeneration…”

α-Synuclein and dopamine at the crossroads of Parkinson's disease. by Venda, L, Cragg, S, Buchman, V, Wade-Martins, R

“…Here we ask why these neurons are preferentially susceptible to neurodegeneration in PD and how α-synuclein is involved. …”

Gene therapy restores dopamine transporter expression and ameliorates pathology in iPSC and mouse models of infantile parkinsonism by Ng, J, Barral, S, De La Fuente Barrigon, C, Lignani, G, Erdem, FA, Wallings, R, Privolizzi, R, Rossignoli, G, Alrashidi, H, Heasman, S, Meyer, E, Ngoh, A, Pope, S, Karda, R, Perocheau, D, Baruteau, J, Suff, N, Antinao Diaz, J, Schorge, S, Vowles, J, Marshall, LR, Cowley, SA, Sucic, S, Freissmuth, M, Counsell, JR, Wade-Martins, R, Heales, SJR, Rahim, AA, Bencze, M, Waddington, SN, Kurian, MA

“…Using patient-derived induced pluripotent stem cells (iPSCs), we generated a midbrain dopaminergic (mDA) neuron model of DTDS that exhibited marked impairment of DAT activity, apoptotic neurodegeneration associated with TNFα-mediated inflammation, and dopamine toxicity. …”

The effect of alpha-synuclein knockdown on MPP+ toxicity in models of human neurons. by Fountaine, T, Venda, L, Warrick, N, Christian, H, Brundin, P, Channon, K, Wade-Martins, R

“…The protein alpha-synuclein is central to the pathophysiology of Parkinson's disease (PD) but its role in the development of neurodegeneration remains unclear. alpha-Synuclein-knockout mice develop without gross abnormality and are resistant to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), a mitochondrial inhibitor widely used to model parkinsonism. …”

Cellular reprogramming: a new approach to modelling Parkinson's disease. by Hartfield, E, Fernandes, H, Vowles, J, Cowley, S, Wade-Martins, R

“…In comparison, iPSCs provide a living cell model with the potential to study early molecular changes which accumulate in cells and ultimately result in neurodegeneration. Although clear phenotypes have not yet been unambiguously identified in patient-derived dopaminergic neurons, there are suggested aberrations in cellular pathways involved in neurodegeneration. …”

Multiparameter phenotypic screening for endogenous TFEB and TFE3 translocation identifies novel chemical series modulating lysosome function by Carling, PJ, Ryan, BJ, McGuinness, W, Kataria, S, Humble, SW, Milde, S, Duce, JA, Kapadia, N, Zuercher, WJ, Davis, JB, Di Daniel, E, Wade-Martins, R

“…The amelioration of disease phenotypes across multiple models of neurodegeneration can be achieved through modulating the master regulator of lysosome function, TFEB (transcription factor EB). …”

Haplotype-specific expression of exon 10 at the human MAPT locus by Caffrey, T, Joachim, C, Paracchini, S, Esiri, M, Wade-Martins, R

“…These data may explain the increased susceptibility of H1 carriers to neurodegeneration and suggest a potential mechanism between MAPT genetic variability and the pathogenesis of neurodegenerative disease.…”

Haplotype-specific expression of exon 10 at the human MAPT locus. by Caffrey, T, Joachim, C, Paracchini, S, Esiri, M, Wade-Martins, R

“…These data may explain the increased susceptibility of H1 carriers to neurodegeneration and suggest a potential mechanism between MAPT genetic variability and the pathogenesis of neurodegenerative disease.…”

Tau depletion in human neurons mitigates Aβ-driven toxicity by Ng, B, Vowles, J, Bertherat, F, Abey, A, Kilfeather, P, Beccano-Kelly, D, Stefana, MI, O’Brien, DP, Bengoa-Vergniory, N, Carling, PJ, Todd, JA, Caffrey, TM, Connor-Robson, N, Cowley, SA, Wade-Martins, R

“…Cortical neurons derived from these iPSC lines showed that tau is essential in Aβ-driven hyperactivity, axonal transport deficits, and neurodegeneration, consistent with studies conducted in Mapt−/− mouse models. …”

Mitochondrial dysfunction and mitophagy in Parkinson's: from familial to sporadic disease. by Ryan, B, Hoek, S, Fon, E, Wade-Martins, R

“…Recently, the mechanisms by which PD-associated mitochondrial proteins phosphatase and tensin homolog deleted on chromosome 10 (PTEN)-induced putative kinase 1 (PINK1) and parkin function and induce neurodegeneration have been identified. In addition, increasing evidence implicates other PD-associated proteins such as α-synuclein (α-syn) and leucine-rich repeat kinase 2 (LRRK2) in mitochondrial dysfunction in genetic cases of PD with the potential for a large functional overlap with sporadic disease. …”

A novel method for autophagy detection in primary cells: impaired levels of macroautophagy in immunosenescent T cells. by Phadwal, K, Alegre-Abarrategui, J, Watson, A, Pike, L, Anbalagan, S, Hammond, E, Wade-Martins, R, McMichael, A, Klenerman, P, Simon, A

“…Autophagy plays a role in many diseases such as neurodegeneration and cancer; however, to date, conventional autophagy detection techniques are not suitable for clinical samples. …”

Haplotype-specific expression of the N-terminal exons 2 and 3 at the human MAPT locus. by Caffrey, T, Joachim, C, Wade-Martins, R

“…We suggest that inclusion of exon 3 in MAPT transcripts may contribute to protecting H2 carries from neurodegeneration.…”

The role of MAPT sequence variation in mechanisms of disease susceptibility. by Caffrey, T, Wade-Martins, R

“…The microtubule-associated protein tau (MAPT or tau) is of great interest in the field of neurodegeneration as there is a well-established genetic link between the MAPT gene locus and tauopathies, a diverse group of neurodegenerative dementias and movement disorders. …”

Identification of distinct circulating exosomes in Parkinson's disease. by Tomlinson, P, Zheng, Y, Fischer, R, Heidasch, R, Gardiner, C, Evetts, S, Hu, M, Wade-Martins, R, Turner, M, Morris, J, Talbot, K, Kessler, B, Tofaris, G

“…Accordingly, we showed in models of neuronal stress that Parkinson's-derived microvesicles have a protective effect.Collectively, these data suggest for the first time that immunophenotyping of circulating exosome subpopulations in PD may lead to a better understanding of the systemic response to neurodegeneration and the development of novel therapeutics.…”

Oxidation Resistance 1 Modulates Glycolytic Pathways in the Cerebellum via an Interaction with Glucose-6-Phosphate Isomerase by Finelli, M, Paramo, T, Pires, E, Ryan, B, Wade-Martins, R, Biggin, P, McCullagh, J, Oliver, P

“…Here, we investigated the molecular mechanisms driving the selective neurodegeneration in an ataxic mouse model lacking oxidation resistance 1 (Oxr1) and discovered an unexpected function for this protein as a regulator of the glycolytic enzyme, glucose-6-phosphate isomerase (GPI/Gpi1). …”

Targeting alpha-synuclein as a therapy for Parkinson’s disease by Fields, CR, Bengoa-Vergniory, N, Wade-Martins, R

“…Moreover, alpha-synuclein is present in Lewy-bodies, the neuropathological hallmark of PD, and the protein and its aggregation have been widely linked to neurotoxic pathways that ultimately lead to neurodegeneration. Such pathways include autophagy/lysosomal dysregulation, synaptic dysfunction, mitochondrial disruption, and endoplasmic reticulum (ER) and oxidative stress. …”

Mitochondrial dysfunction and mitophagy in Parkinson’s disease: From mechanism to therapy by Malpartida, AB, Williamson, M, Narendra, DP, Wade-Martins, R, Ryan, BJ

“…Mitochondrial dysfunction has been associated with neurodegeneration in Parkinson’s disease (PD) for over 30 years. …”

RNA interference-mediated knockdown of alpha-synuclein protects human dopaminergic neuroblastoma cells from MPP(+) toxicity and reduces dopamine transport. by Fountaine, T, Wade-Martins, R

“…The critical observation in the pathology of Parkinson's disease (PD) is that neurodegeneration is largely restricted to dopaminergic neurons that develop cytoplasmic inclusions called Lewy bodies. …”