Ravindran Kumaran

Publications (5)26.03 Total impact

• Article: LRRK2 expression in idiopathic and G2019S positive Parkinson's disease subjects: a morphological and quantitative study.

  S Sharma, R Bandopadhyay, T Lashley, A E M Renton, A E Kingsbury, R Kumaran, C Kallis, C Vilariño-Güell, S S O'Sullivan, A J Lees, T Revesz, N W Wood, J L Holton
  [show abstract] [hide abstract]
  ABSTRACT: Mutations in the gene encoding leucine-rich repeat kinase-2 (LRRK2) have been established as a common genetic cause of Parkinson's disease (PD). The distribution of LRRK2 mRNA and protein in the human brain has previously been described, although it has not been reported in PD cases with the common LRRK2 G2019S mutation. To further elucidate the role of LRRK2 in PD, we determined the localization of LRRK2 mRNA and protein in post-mortem brain tissue from control, idiopathic PD (IPD) and G2019S positive PD cases. Widespread neuronal expression of LRRK2 mRNA and protein was recorded and no difference was observed in the morphological localization of LRRK2 mRNA or protein between control, IPD and G2019S positive PD cases. Using quantitative real-time polymerase chain reaction, we demonstrated that there is no regional variation in LRRK2 mRNA in normal human brain, but we have identified differential expression of LRRK2 mRNA with significant reductions recorded in limbic and neocortical regions of IPD cases compared with controls. Semi-quantitative analysis of LRRK2 immunohistochemical staining demonstrated regional variation in staining intensity, with weak LRRK2 immunoreactivity consistently recorded in the striatum and substantia nigra. No clear differences were identified in LRRK2 immunoreactivity between control, IPD and G2019S positive PD cases. LRRK2 protein was identified in a small proportion of Lewy bodies. Our data suggest that widespread dysregulation of LRRK2 mRNA expression may contribute to the pathogenesis of IPD.
  Neuropathology and Applied Neurobiology 06/2011; 37(7):777-90. · 3.80 Impact Factor
• Article: Differential DJ-1 gene expression in Parkinson's disease.

  Ravindran Kumaran, Jana Vandrovcova, Connie Luk, Simone Sharma, Alan Renton, Nicholas W Wood, John A Hardy, Andrew J Lees, Rina Bandopadhyay
  [show abstract] [hide abstract]
  ABSTRACT: Mutations in the DJ-1 gene have been linked with rare cases of early onset, autosomal recessive Parkinson's disease (PD). To determine whether DJ-1 is also involved in the pathogenesis of common forms of PD we have compared DJ-1 mRNA levels in a number of post-mortem PD and control brain regions using quantitative real-time PCR. Region-specific decreases were observed in DJ-1 mRNA levels in putamen, frontal cortex, parietal cortex and cerebellum in PD ( approximately 30-60%) compared to controls whilst an up-regulation was observed in the amygdala ( approximately 90%) and entorhinal cortex ( approximately 39%). Using quantitative western blot analysis, parallel decreases in DJ-1 protein levels were seen in frontal cortex, putamen and cerebellum of PD cases. By using 2-dimensional gel electrophoresis, we show preponderance of acidic pI isoforms of DJ-1 monomer in PD vulnerable regions, namely frontal cortex and medulla suggestive of differential post-translational modifications. Our findings point to a putative role of DJ-1 in the pathogenesis of PD.
  Neurobiology of Disease 09/2009; 36(2):393-400. · 5.40 Impact Factor
• Article: TDP-43 in ubiquitinated inclusions in the inferior olives in frontotemporal lobar degeneration and in other neurodegenerative diseases: a degenerative process distinct from normal ageing.

  Yvonne Davidson, Hanan Amin, Thomas Kelley, Jing Shi, Jinzhou Tian, Ravindran Kumaran, Tammaryn Lashley, Andrew J Lees, Daniel DuPlessis, David Neary, Julie Snowden, Haruhiko Akiyama, Tetsuaki Arai, Masato Hasegawa, Rina Bandopadhyay, Steve Sikkink, Stuart Pickering-Brown, David M A Mann
  [show abstract] [hide abstract]
  ABSTRACT: Ubiquitin immunoreactive (UBQ-ir) inclusions were present to variable extents in the inferior olivary nucleus (ION) in 37/48 (77%) patients with frontotemporal lobar degeneration (FTLD), in 10/11 (91%) patients with motor neurone disease (MND), in 5/5 (100%) patients with Alzheimer's disease (AD), 5/7 (71%) patients with dementia with Lewy bodies, 13/19 (68%) patients with Parkinson's disease, 11/11(100%) patients with Progressive Supranuclear Palsy, 2/6 (33%) patients with Multisystem Atrophy, 1/3 (33%) patients with Huntington's disease and in 14/14 (100%) normal elderly control subjects. In FTLD, UBQ-ir inclusions were present in 26/32 (81%) patients with FTLD-U, in 10/15 (67%) patients with tauopathy, and in the single patient with Dementia Lacking Distinctive Histology. In 13 FTLD-U patients, and in a single AD and in 2 MND patients, the UBQ-ir inclusions had a rounded, spicular or skein-type appearance, and these were also TDP-43 immunoreactive (TDP-43-ir). In all other affected patients in all diagnostic groups, and in control subjects, the UBQ-ir neuronal cytoplasmic inclusions (NCI) were of a conglomerated type, resembling a cluster of large granules or globules, but were never TDP-43-ir. In 3 of the 13 FTLD-U patients with spicular NCI, conglomerated NCI were also present but in separate cells. Double-labelling immunohistochemistry, and confocal microscopy, for UBQ and TDP-43 confirmed that only the spicular UBQ-ir inclusions in patients with FTLD-U, AD and MND contained TDP-43, though in these patients there were occasional TDP-43 immunoreactive inclusions that were not UBQ-ir. Nuclear TDP-43 immunoreactivity was absent in ION in FTLD-U, AD or MND when TDP-43 cytoplasmic inclusions were present, but remained in neurones with UBQ-ir, TDP-43 negative inclusions. The target protein within the UBQ-ir, TDP-43-negative inclusions remains unknown, but present studies indicate that this is not tau, neurofilament or internexin proteins. These TDP-43 negative, UBQ-ir inclusions appear to be more related to ageing than neurodegeneration, and are without apparent diagnostic significance. The pathophysiological mechanism leading to their formation, and any consequences their presence may have on nerve cell function, remain unknown.
  Acta Neuropathologica 04/2009; 118(3):359-69. · 9.32 Impact Factor
• Article: Post-transcriptional regulation of mRNA associated with DJ-1 in sporadic Parkinson disease.

  Jeff Blackinton, Ravindran Kumaran, Marcel P van der Brug, Rili Ahmad, Lars Olson, Dagmar Galter, Andrew Lees, Rina Bandopadhyay, Mark R Cookson
  [show abstract] [hide abstract]
  ABSTRACT: Mutations in DJ-1 lead to a monogenic form of early onset recessive parkinsonism. DJ-1 can respond to oxidative stress, which has been proposed to be involved in the pathogenesis of sporadic Parkinson disease (PD). We have recently reported that DJ-1 interacts with mRNA in an oxidation-dependent manner. Here, we confirm interaction of DJ-1 and RNA in human brain using immunoprecipitation followed by quantitative real time PCR. We confirmed previous reports that DJ-1 is more oxidized in cortex from cases of sporadic PD compared to controls. In the same samples, protein and RNA expression was measured for four DJ-1 target genes GPx4, MAPK8IP1, ND2 and ND5. While no alterations in mRNA expression were observed, an increase in protein expression was observed in PD cases for GPx4 and MAPK8IP1. In the same patients, we saw decreased mRNA and protein levels of two mitochondrial targets, ND2 and ND5. These results suggest that these proteins undergo regulation at the post-transcriptional level that may involve translational regulation by DJ-1.
  Neuroscience Letters 02/2009; 452(1):8-11. · 2.11 Impact Factor
• Article: DJ-1 (PARK7) is associated with 3R and 4R tau neuronal and glial inclusions in neurodegenerative disorders.

  Ravindran Kumaran, Ann Kingsbury, Ian Coulter, Tammaryn Lashley, David Williams, Rohan de Silva, David Mann, Tamas Revesz, Andrew Lees, Rina Bandopadhyay
  [show abstract] [hide abstract]
  ABSTRACT: Mutations in the DJ-1 gene are associated with autosomal recessive Parkinson's disease (PD), but its role in disease pathogenesis is unknown. This study examines DJ-1 immunoreactivity (DJ-1 IR) in a variety of neurodegenerative disorders, Alzheimer's disease (AD), frontotemporal lobar degeneration (FTLD) with Pick bodies, FTLD with MAPT mutations, progressive supranuclear palsy (PSP) and corticobasal degeneration (CBD), in which hyperphosphorylated tau inclusions are the major pathological signature. DJ-1 IR was seen in a subset of neurofibrillary tangles (NFTs), neuropil threads (NTs), and neurites in extracellular plaques in AD; tau inclusions in AD contained both 3R and 4R tau. A subset of Pick bodies in FTLD showed DJ-1 IR. In PSP, DJ-1 IR was present in a few NFTs, NTs and glial cell inclusions. In CBD, DJ-1 IR was seen only in astrocytic plaques. In cases of FTLD with MAPT mutations that were 4R tau positive (i.e. N279K and exon 10+16 mutations), DJ-1 IR was present mostly in oligodendroglial coiled bodies. However, in MAPT R406W mutation cases, DJ-1 IR was associated mainly with NFTs and NTs and these were both 3R and 4R tau positive. No DJ-1 IR was present in FTLD with ubiquitin inclusions (FTLD-U). In AD and FTLD with Pick bodies, DJ-1 protein was enriched in the sarkosyl-insoluble fractions of frozen brain tissue containing insoluble hyperphosphorylated tau, thus strengthening the association of DJ-1 with tau pathology. Additionally using two-dimensional gel electrophoresis, we demonstrated accumulation of acidic pI isoforms of DJ-1 in AD brain, which may compromise its normal function. Our observations confirm previous findings that DJ-1 is present in a subpopulation of glial and neuronal tau inclusions in tau diseases and associated with both 3R and 4R tau isoforms.
  Neurobiology of Disease 11/2007; 28(1):122-32. · 5.40 Impact Factor