P11: The influence of cGMP signaling in Alzheimer’s disease (from 01.01.2025)

Aims

This project builds on emerging evidence of the interplay between the actomyosin network and microtubules in neurons, a largely unexplored area. Previous studies have shown that tau protein aggregation, a hallmark of Alzheimer’s disease, results from its dissociation from microtubules. Additionally, destabilization of actin-spectrin rings is known to affect microtubule stability and vice versa. In this study, we will investigate the role of cGMP in regulating actomyosin contractility and its impact on microtubule dynamics and tau aggregation, with the goal of uncovering potential therapeutic targets.

Questions and Methods

cGMP and cytoskeleton mechanics in neurodegenerative disease

> What are the functional effects of cGMP in AD-associated axonal swellings of cortical neurons?
> Does cGMP modulate the microtubule network in these neurons?
> Can clinically used cGMP-elevating drugs (e.g., NO-GC stimulators, PDE inhibitors) reverse axonal swellings?
> Is there a direct connection between cGMP-related pathways and tau phosphorylation?

Boston Internship

(to be determined)

Doctoral Students

Jaya Mishra

Jaya Mishra obtained her bachelor's degree in Biotechnology Engineering at SRM Institute of Science and Technology, India, where she developed a deep interest in neuroscience, particularly neurodegeneration. In her bachelor thesis, she explored key molecular mechanisms underlying neurodegenerative diseases. Jaya continued her studies with a consecutive master’s program and completed her MSc in Neuroscience at King’s College London, specializing in neurodegenerative diseases. Here, she investigated genetic and non-genetic factors contributing to the late onset of Alzheimer’s and Parkinson’s disease. After obtaining her MSc degree, Jaya moved to Tübingen to gain clinical research experience at the Hertie Institute for Brain Research. She then decided to continue her academic journey and joined Dr. Rafiq’s group for her doctoral studies in August 2024. Today, she is researching the role of physical forces in the dissociation of tau protein from microtubules and exploring novel mechanisms of tau seeding. Additionally, she is investigating non-classical synapses in Parkinson’s disease models, specifically in the context of LRRK2 mutations, using neural stem cells as a model system. To further characterize proteins associated with synaptic assemblies, she is also developing a non-neuronal system to study synaptic mechanisms from an alternative perspective.

Key Publications

Fujise K, Mishra J, Rosenfeld M, Rafiq NM. Synaptic vesicle characterization of iPSC-derived dopaminergic neurons provides insight into distinct secretory vesicle pools. NPJ Parkinsons Dis. (2025).

Rafiq NM*, Fujise K, Rosenfeld M, Xu Peng, De Camilli P*. Parkinsonism mutation in Synaptojanin 1 affects primary cilia in iPSC-derived dopaminergic neurons. PNAS. (2024)
*co-corresponding author

Rafiq NM, Lyons L, Gowrishankar S, De Camilli P, Ferguson S. JIP3 links lysosome transport to regulation of multiple components of the axonal cytoskeleton. Communications Biology. (2022).

Rafiq NBM, Nishimura Y, Plotnikov SV, Thiagarajan V, Zhang Z, Natarajan M, Shi S, Viasnoff V, Jones GE, Kanchanawong P, Jones GE, Bershadsky AD. A mechano-signaling network linking microtubules, myosin-IIA filaments and integrin-based adhesions. Nature Materials. (2019).

Rafiq NBM, Grenci G, Lim CK, Kozlov ME, Jones GE, Viasnoff V, Bershadsky AD. Forces and constraints controlling podosome assembly and disassembly. Philos Trans R Soc Lond B Biol Sci. (2019).

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