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Dr. Harsha Kantamneni

Associate Professor

Area
School of Pharmacy & Medical Sciences
Faculty of Life Sciences
E-mail
S.Kantamneni@bradford.ac.uk
Phone
+441274236072
Dr. Harsha Kantamneni
7 research projects
14 publications

Research


Research projects

Date
Role
PI

Sporadic motor neuron disease (MND) accounts for around 90% of cases with the remaining 10% being inherited. However, the mechanisms causing disease are often indistinguishable, suggesting that functional analysis of genes linked with inherited MND can identify mechanisms underlying sporadic cases. Studies in multiple patient cohorts have shown that inactivating mutations in the TBK1 (TANK binding kinase 1) gene cause both inherited and sporadic MND & frontotemporal dementia. TBK1 interacts with and phosphorylates optineurin and p62, promotes mitophagy and is part of a common pathway known to regulate autophagy and neurodegeneration. SOCS3 (suppressor of cytokine signalling 3) is an inducible protein that binds and regulates the ubiquitination and degradation of specific substrates, including TBK1. As SOCS3 down-regulates TBK1 expression, we hypothesise that disruption of the SOCS3-TBK1 interface in neurons can rescue TBK1 function by decreasing its degradation and thus represents a tractable new target for therapeutic intervention to limit neurodegeneration in MND.

Date
Role
PI

Protein degradation is of fundamental importance for neuronal function and perturbation of degradative pathways has been implicated in multiple neurodegenerative disorders but particularly Alzheimers disease (AD). ESCRT proteins mediate trafficking of membrane proteins to lysosomes and their degradation. ESCRT consists of four multiprotein complexes (ESCRT–0, –I, –II and –III) that mediate endocytosis of cell surface proteins including glutamate receptors (Kantamneni et al., 2009) through multivesicular bodies (MVBs) to lysosomes for degradation. Previously, ESCRT-III subunit CHMP2B immunopositivity has been identified in granulovacuolar degeneration bodies in neurons of AD hippocampus. One of the key feature of early onset AD models is the intracellular amyloid-β (Aβ) accumulation that precedes the appearance of Aβ in extracellular plaques. Recently it has been shown that Aβ is generated through proteolytic processing of amyloid precursor protein (APP), which is localised to MVBs and that it is delivered to lysosomes for degradation. Transient depletion of either ESCRT-0 or -I components, inhibited targeting of APP to MVBs and the subsequent delivery to lysosomes. This resulted in increased intracellular Aβ accumulation, accompanied by dramatically decreased Aβ secretion. In summary, ESCRT machinery has multiple roles in limiting intracellular Aβ accumulation through targeting of APP to the lysosomes for degradation as well as trafficking & degradation of neurotransmitters receptors. Based on these observations, my lab is testing the hypothesis that, since in AD models ESCRTs function is abnormal, studying ESCRT mechanisms and its regulation in neurons has the potential to identify new molecular targets for therapeutic intervention in AD.

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PI

GABAB receptors are heterodimers of GABAB1 and GABAB2 subunits and require both subunits for functional signalling. Previously I have shown that exposing neurons to extreme metabolic stress using oxygen/glucose deprivation (OGD) ischemic model, increases GABAB1 but decreases GABAB2 surface expression in neurons. The increase in surface GABAB1 involves enhanced recycling and is blocked by the NMDA receptor-selective antagonist AP5. The decrease in surface GABAB2 is also blocked by AP5 and by inhibiting degradation pathways. These results indicate that NMDAR activity is a critical regulator of GABABR trafficking and function to regulate neuronal responsiveness and survival. Building on this work, I hypothesize that the loss of NMDA receptor-mediated inhibition represents a novel mechanism by which excitotoxicity triggers the death of damaged neurons. May 2017; Alzheimer’s Research Trust Network (PI): The SOCS3/TBK1 interface: An opportunity for development of novel therapeutics to prevent MND and neurodegeneration March 2016; Alzheimer’s Research UK - Yorkshire regional network (PI): ESCRT proteins as therapeutic targets in Alzheimers disease March 2016; Royal Society (PI): Mechanisms regulating NMDA-mediated down-regulation of neuronal GABAB receptors in ischemia

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Co-PI

ARUK

Professional activities

  • Member of Biochemical Society,
  • Member of British Pharmacological Society,
  • Member of British Neuroscience Association,
  • Member of International Society for Neurochemistry,
  • Member of British Society for Cell Biology,

  • University of Bradford - postgraduate certificate
  • Sheffield Hallam University - MSc
  • City of Bristol College - APD
  • DR. MGR Medical University, India - Bachelors
  • University of Bristol - PhD

  • King Faisal Specialist Hospital, Riyadh, Saudi Arabia - Research Fellow (1 January 2011)
  • University of Bristol - Research Associate (1 January 2005)

Publications