Intersections of diabetes and Parkinson's disease suggest parallel mechanisms leading to trophic factor resistance

Raised of $12,000 Goal
Ended on 1/12/22
Campaign Ended
  • $2,925
  • 25%
  • Finished
    on 1/12/22

About This Project

Insulin and exercise improves diabetes, AD and PD. In diabetes, resident immune cells (RICs) secrete inflammatory cytokines upon ingestion of fat deposits, inhibiting Akt signaling. Glial derived neurotrophic factor (GDNF) also activates Akt. Perhaps a similar mechanism occurs in the CNS, involving RIC exposure to alpha-synuclein aggregates. We will attempt to replicate this in vitro and characterize RIC inflammatory status, then expose neuronal lines to RIC and monitor Akt inhibition.

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What is the context of this research?

Studies have suggested that dementia has a possible connection to diabetes. A major component of type 2 diabetes, RICs secrete inflammatory signals that oppose the action of insulin. Due to my experience with peripheral neurodegeneration, I was offered an opportunity to design a project focusing on central neurodegeneration. This proposal was prompted by other studies which have shown that insulin or exercise corrects peripheral diabetes and also a number of neurodegenerative insults in the CNS. Insulin or neurotrophic factors GDNF activate Akt protein. Loss of Akt activation leads to dysfunction and/or cell death peripherally and centrally, thus Akt is an essential signal of robust trophic support and vitality.

What is the significance of this project?

This study may provide evidence that inflammatory signaling can lead to a inhibition of trophic response within the CNS. Improper trophic response impairs cell function and can lead to cell death. Thus, neurotrophic factor resistance may be viewed as a novel mechanism for neurodegeneration. Therapies can be designed which enhance Akt signal or block the inflammatory signals which inhibit Akt signaling in the CNS. For example, administration of intranasal insulin improves symptoms and pathologies of PD, AD and traumatic brain injury. Lastly, RIC response to alpha-synuclein deposits (aSyn), may suggest a unifying theme for diseases of aggregation. There may be other diseases which have interstitial aggregation in common to their pathologies, a few of which are type2 diabetes, PD, and AD.

What are the goals of the project?

Alpha-synuclein (aSyn) synthetic aggregates like the aSyn deposits found in PD (PDf) or control aSyn (CTf) will be applied to a microglial cell line (uG). We expect that PDf treated uG cells to become inflammatory, and that CTf treated cells will change minimally, confirmed via measurement of inflammatory signal. Collected media from the treated uG cells will be applied to a neuronal cell line similar to the neurons which are affected in PD. Trophic signal will be measured by phospho-Akt in neuronal cells basally, or treated with glial derived neurotrophic factor (GDNF). We predict that in GDNF stimulated PDf vs CTf treated neuronal cells, the Akt response will be blunted in PDf compared to CTf uG treated neuronal cells , indicating resistance to trophic stimulus.


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This study is preliminary, this data will be used for a larger in vivo proposal, addressing our hypothesis in greater detail and rigor. We have already observed in vivo the loss of motor coordination and restoration with exercise in a rat model of PD (see additional information). We have evidence which suggests that RICs may be polarized to inflammatory phenotypes in a Parkinson's disease rat model and switched to a restorative phenotype with exercise, a process which is strikingly similar to exercise therapy in diabetics. These funds will be used to show proof of principle in vitro.

Endorsed by

This is an interesting project that has the potential to yield new insights into Parkinson's disease. Dr. Groshong has the necessary training an motivation to carry out these studies. I am happy to endorse this project.
This is an excellent research proposal by a well-trained neuroscientist. Completion of this proposal will provide new insight into the mechanisms of Parkinson’s induced neuropathy. Moreover, Dr. Groshong is going to involve undergraduate students in this research. What an exciting opportunity for undergraduate students to participate and learn various research techniques from Dr. Groshong!
This is an excellent research proposal by a well-trained neuroscientist. Completion of this proposal will provide new insight into the mechanisms of Parkinson’s induced neuropathy. Moreover, Dr. Groshong is going to involve undergraduate students in this research. What an exciting opportunity for undergraduate students to participate and learn various research techniques from Dr. Groshong!
This is a thoughtful project with an excellent premise and enticing hypothesis. Dr. Groshong has the background skills and drive to carry out this project. The project can be done and should be done.
Jason Groshong, Ph.D. Has developed a unique insight to the mechanisms involved in systemic stressors and central nervous system degeneration. I am excited that he is combining his extensive, cross-discipline research background on this new hypothesis of neurodegeneration. Jason is uniquely suited to succeed in this research, and the results from this effort could bring about a new understanding in the mechanisms of neurodegeneration.

Project Timeline

This is roughly a six month timeline to gather the necessary data to show proof of principle using our proposed model. By taking a stepwise, focused approach we expect to be able to find the weaknesses in our methodology and correct them before we move forward in complexity. These time points highlight sharable milestones with our backers and provide transparent evidence of progress.

Dec 13, 2021

Project Launched

Dec 31, 2021

Succesful funding campaign-acquire raw materials

Jan 31, 2022

Establish cell lines and culture system

Feb 28, 2022

Optimize fibril treatments

Mar 31, 2022

Optimize measurement of inflammatory status

Meet the Team

Jason S Groshong
Jason S Groshong
Visiting Professor


University of St. Thomas
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Team Bio

Jason seeks to mentor a sprouting new scientist with these funds. Thus, an undergraduate researcher will be working closely with me, receiving an authentic research experience. With the data gathered, we will apply for an NIH R15 grant which is uniquely suited to strengthen the legacy of undergraduate research at the University of St. Thomas in St. Paul, Minnesota.

Jason S Groshong

Jason studies mechanism of disease, with topics ranging from peripheral and central neurodegeneration, muscle biology, cancer biology, diabetes and obesity. He currently focuses on the parallels between Diabetes, Parkinson's, and Alzheimer's disease, something that has fascinated him for about 20 years now.

Additional Information

Rotenone treatment in rats leads to a decrement while rotenone plus exercise leads to a restoration of latency to fall by rotarod test when compared with controls (A). Additionally rotenone (RO) treatment leads to a decrease in TH enzyme level in the substantia nigra pars compacta (pink region), which is restored when exercise is applied to rotenone treatment (RE) compared with controls (CT) as shown by western blot (B) and near infrared immunohistochemistry (C) with quantification by counts (D). Unpublished results.

Hstological morphology and surface marker density of microglia suggests phenotypes are different when exercise is applied to the rat rotenone model. Pan microglial marker CD11b detection increases with RO when compared to controls, gliosis remains elevated in RE. The restorative M2 migroglial surface marker (CD68) coexpressed with CD11b was quantified. RO treatment decreased CD68 and RE lead to a partial sparing of CD68 when compared to controls. Unpublished results

Taken together these results suggest the microglial phenotype changes with rotenone treatment to an inflammatory mode of action (M1), and that exercise improves motor coordination and neuronal function associated with a sparing of a restorative microglial phenotype (M2).

Project Backers

  • 16Backers
  • 25%Funded
  • $2,925Total Donations
  • $182.81Average Donation
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