Mohanish Deshmukh
University of North Carolina at Chapel Hill, NC·Neuroscience
Neurons in the adult brain must keep working for decades, yet many weaken and die with age or disease. This research asks two linked questions.
- Fields
Neuroscience
Genetics
Biology
- Topics
Alzheimer's disease
neurodegeneration
miR-29
- Grants
- 3 known grants, through Dec 2027
What they work on
- Identify which brain cell types are most affected when miR-29, a microRNA that rises during brain maturation, is reduced in the adult mouse brain, using single-cell RNA sequencing and analysis of dendritic spines and neuron branching.
- Test whether excess CH methylation, an unusual DNA tagging pattern controlled by miR-29 through the enzyme Dnmt3a, is a common feature of Alzheimer's disease in three mouse models and in patient brain samples.
- Evaluate whether restoring miR-29 with AAV, a harmless virus used to deliver genes, protects neurons in human stem-cell and preclinical mouse models of Alzheimer's disease.
- Map where caspases, the enzymes that execute cell death, become active in the cell body versus the axons during apoptosis and pruning, using neurons grown in microfluidic chambers that separate the two compartments.
- Test whether confined caspase activity 'cuts off' axons and triggers the Sarm1 axon-degeneration pathway, and examine Sarm1-deficient mice for pruning defects and behavioral deficits.
- Identify which inflammasome proteins, immune-signaling complexes that activate caspase-1, are essential for axon pruning in NGF-deprived sympathetic neurons, and define the roles of IL-1β and IL-18 and how NLRP1 is activated.
- Test whether NLRP1 drives amyloid-beta-induced degeneration of axons and synapses, using a microfluidic culture model and an Alzheimer's disease mouse model lacking NLRP1.
More about the research
First, what molecular programs keep mature neurons healthy over the long term? Second, how do neurons deliberately destroy parts of themselves? A neuron can die entirely through apoptosis, a built-in form of programmed cell death. It can also trim selected branches of its axons, the long cable-like extensions that carry signals, in a process called axon pruning. Both questions connect to Alzheimer's disease (AD), in which neurons lose their connections and die.
Why it matters
Alzheimer's disease destroys the connections between neurons and has few effective treatments. This work could point to new therapeutic directions. One is restoring miR-29 in the aging brain, which the project tests with gene delivery in mouse and human stem-cell models of AD. Another is blocking NLRP1-driven loss of axons and synapses. Clarifying how neurons normally prune axons during development may also show how this process goes wrong in neurodegeneration.
Known grants
From NIH and NSF research grants. Labs often have other funding we can't see.
Closest labs
Anne-Marie Malfait
Rush University, IL·Neuroscience
Map nerve fibers and gene activity in skin from classic Ehlers-Danlos syndrome patients versus controls, using tissue staining and Visium spatial transcriptomics, which measures gene activity across tissue slices.
Alexandra Byrne
University of Massachusetts Chan Medical School, MA·Neuroscience
Determine how TIR-1/SARM1, a conserved protein that usually drives axon degeneration, instead protects C. elegans neurons from damage caused by excess acetylcholine receptor activity or paraquat-induced oxidative stress.
Riqiang Yan
University of Connecticut, CT·Neuroscience
Identify potent short peptides from the CX3CL1 C-terminal domain (CX3CL1-ICD), a neuron-protecting protein region, that reduce Alzheimer's pathology and cell death in neurons and AD mouse models.
The school
University of North Carolina at Chapel Hill: 72 labs on PI Pages, $1.6B a year on research, 523 research doctorates a year.
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