Jonathan Cooper, Ph.D.


Developmental, Regenerative and Stem Cell Biology Program
Neurosciences Program
Molecular Genetics and Genomics Program

  • 314 273-9067

  • 314 273-9066

  • MPRB 5th Floor


  • @Batten_PSDL

  • Batten Disease, Neuronal Ceroid Lipofuscinosis, NCL, Lysosomal Storage Disease, pathogenesis, pre-clinical therapies, enzyme replacement, gene therapy

  • Studying the pathogenesis of Batten disease and other lysosomal storage disorders

Research Abstract:

1. The early stages of my career were spent investigating the influence of target-derived neurotrophins upon neurons of the cholinergic basal forebrain and how this altered during development, different stages of maturation and in aging. This revealed significant new information about how in these different contexts neurotrophins such as NGF, BDNT and NT-3 variably influenced neuron survival, or phenotype. This was a prelude to investigating the same issues in a mouse model of Down syndrome, revealing that the failure of retrograde transport of NGF contributed to the apparent loss of cholinergic neurons, but that these ‘phenotypically silent’ neurons could be rescued by administration of NGF.

2. The first phase of my work on the neuronal ceroid lipofuscinoses (NCLs or Batten disease) involved answering fundamental questions about how the brain is affected and the staging of pathology in these disorders. This work for the first time defined which neuron populations are affected, revealing that it is remarkably selective in the early stages of pathogenesis. The first vulnerable neuron population to be identified was GABAergic interneurons, followed by the staging of neuron loss within the thalamocortical system, which revealed the thalamus as an unexpected pathological target in these disorders. We also demonstrated the selective effects upon populations of cerebellar neurons, and have continued this work to reveal an unexpectedly severe pathology in the brainstem and spinal cord. More recently we have revealed the involvement of the peripheral, autonomic and enteric nervous systems and are investigating their contribution to disease outcome.

3. Following these discoveries we have been working to understand the selective nature of neuron loss in the NCLs and what might influence this. By comparing the relative timing and distribution of neuron loss to storage material accumulation, astrocytosis and microglial activation we have learnt fundamental lessons about the
staging of NCL pathogenesis and how it differs between disease subtypes. There appears to be no direct correlation between neuron loss and storage material accumulation. Instead there is a much closer correlation
between glial activation and neuron loss, with either astrocytosis or microglial activation consistently preceding
neuron loss, leading us to investigate the nature of neuron:glial interactions and how they may be compromised. Our work has provided evidence that glia are dysfunctional and may directly compromise neuron health, resulting in neuron loss. These studies have highlighted that while different forms of NCL share broad pathological similarities they differ fundamentally in many respects.

4. We have been using the disease landmarks gained through these neuropathological studies to test the efficacy of a variety of pre-clinical experimental therapies. Indeed, we are increasingly asked to undertake this work by a wide-network of academic and industrial collaborators around the world. As such, we have played key roles in studies of gene therapy, neural stem cell transplantation, enzyme replacement, and a variety of small molecule approaches. These include glutamate receptor antagonists, immunosuppressants, and antiinflammatory compounds, with an increasing focus on trying different combinations of experimental therapies in order to potential increase their efficacy. Most recently we identified that treating the brain and spinal cord has a powerful synergistic effect in a mouse model of Cln1 disease. This work has led to several clinical trials including that of mycophenolate mofetil in Cln3 disease, neural stem cell transplants in Cln1 and Cln2 disease, and a successful enzyme eplacement trial in Cln2 disease, which has just been approved by the FDA and EMA as the first ever treatment for CLN2 disease.

Selected Publications:

Vuillemenot BR, Kennedy D, Cooper JD, Wong AM, Sri S, Doeleman T, Katz ML, Coates JR, Johnson GC, Reed RP, Adams EL, Butt MT, Musson DG, Henshaw J, Keve S, Cahayag R, Tsuruda LS, O`Neill CA. Nonclinical evaluation of CNS-administered TPP1 enzyme replacement in canine CLN2 neuronal ceroid lipofuscinosis. Mol Genet Metab. 2015;114(2):281-93. PMID:25257657

Lu JY, Nelvagal HR, Wang L, Birnbaum SG, Cooper JD, Hofmann SL. Intrathecal enzyme replacement therapy improves motor function and survival in a preclinical mouse model of infantile neuronal ceroid lipofuscinosis. Mol Genet Metab. 2015;116(1-2):98-105. PMID:25982063

Aldrich A, Bosch ME, Fallet R, Odvody J, Burkovetskaya M, Rama Rao KV, Cooper JD, Drack AV, Kielian T. Efficacy of phosphodiesterase-4 inhibitors in juvenile Batten disease (CLN3). Ann Neurol. 2016;80(6):909-923. PMCID:PMC5215570 PMID:27804148

Palmieri M, Pal R, Nelvagal HR, Lotfi P, Stinnett GR, Seymour ML, Chaudhury A, Bajaj L, Bondar VV, Bremner
L, Saleem U, Tse DY, Sanagasetti D, Wu SM, Neilson JR, Pereira FA, Pautler RG, Rodney GG, Cooper JD,
Sardiello M. mTORC1-independent TFEB activation via Akt inhibition promotes cellular clearance in
neurodegenerative storage diseases. Nat Commun. 2017;8:14338. PMCID:PMC5303831 PMID:28165011

Last Updated: 1/7/2019 12:46:44 PM

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