Dissecting how SYNJ2 facilitates mrna targeting and translation at neuronal mitochondria
Active Project Grant Awarded Last action
- Award ID
- F31NS141483
- Recipient
-
President And Fellows Of Harvard College UEI JDLVAVGYJQ21 Part of Harvard College President & Fellows Of
- Awarding agency
-
National Institute of Neurological Disorders and Stroke
National Institutes of Health, Department of Health and Human Services
- Obligated
- $211,998
Award facts
- Assistance listing
- 93.853 Extramural Research Programs in the Neurosciences and Neurological Disorders
- Completion date 53% complete
- Place of performance
- Boston, MA 02115, USA
Award details come from USAspending.gov.
Description
- Abstract
- Neurons consume a disproportionate amount of energy compared to other cell types. This heightened oxphos activity helps support membrane polarization and synaptic transmission. Consequently, a single neuron must maintain a mitochondrial network spread throughout the neuropil with spatiotemporal precision. One molecular mechanism to maintain local mitochondrial health is through trafficking of PINK1 mrna. PINK1, a SER/THR kinase mutated in familial forms of parkinson's disease, accumulates on depolarized mitochondria to initiate mitophagy. The schwarz lab has recently demonstrated that PINK1 mrna is CO-trafficked with neuronal mitochondria, including in axons. SYNAPTOJANIN2 (SYNJ2) was identified as the key RNA-binding protein (RBP) that anchors PINK1 mrna to the outer mitochondrial membrane in neurons. Our lab has subsequently created model systems to dissect phenotypes solely dependent on the RNA-binding function of SYNJ2. Specifically, three point mutations in the RNA recognition motif of SYNJ2, which abolishes SYNJ2-mrna interaction, have been introduced in a mouse model and human-derived ipsc neurons. My proposed fellowship research will harness these model systems to investigate the biology behind local mrna trafficking and translation. In specific aim 1, i will determine CIS-regulatory elements that target mrna to mitochondria in a SYNJ2-dependent manner. I will use live mrna imaging, RNA structure prediction, and targeted deletion of candidate sequences to achieve this. Then, in specific aim 2, i will determine if SYNJ2 and/or the outer mitochondrial proteome is required for local translation of PINK1 mrna. To accomplish this, i will artificially tether PINK1 transcripts to mitochondria using viral stem loops, overriding the need for SYNJ2 trafficking. Additionally, i will mistarget PINK1 transcripts to lysosomes. Broadly, my proposed research will elucidate molecular mechanisms underlying decentralized organelle biology in neurons, with important implications for neurodegenerative disease.
Transactions
| Action | Obligated | Date |
|---|---|---|
| Amendment | $38,058 | |
| Amendment | $564 | |
| Amendment | $564 | |
| Amendment | $43,203 | |
| Amendment | $43,203 | |
| Amendment | $0 | |
| Amendment | $43,203 | |
| Amendment | $0 | |
| Amendment | $43,203 | |
| Original award | $0 |
Quick answers
Who received award F31NS141483?
F31NS141483 was awarded to President And Fellows Of Harvard College by National Institute of Neurological Disorders and Stroke (National Institutes of Health) on May 1, 2025.
How much is award F31NS141483 worth?
$211,998 has been obligated on F31NS141483.
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