Joseph R Mazzulli
Northwestern University, IL·Neuroscience
In Parkinson's disease and dementia with Lewy bodies, nerve cells fill up with clumps of protein that the cell can no longer clear away. Why those clumps kill neurons is still unsettled.
- Fields
Neuroscience
Biochemistry
Pharmacology
- Topics
Parkinson's disease
dementia with Lewy bodies
alpha-synuclein
- Grants
- 3 known grants, through May 2031
What they work on
- Determine which messenger RNAs are trapped inside nuclear clumps of the RNA-binding proteins NONO and SFPQ, and how adenosine-to-inosine RNA editing changes where those RNAs sit in patient iPSC-derived cortical and midbrain neurons.
- Test whether stress in mitochondria and in the endoplasmic reticulum-to-Golgi transport route triggers formation of NONO/SFPQ/RNA inclusions, with validation in post-mortem dementia with Lewy bodies brain.
- Use ribosome footprinting, which reads which RNA messages are actively translated, to define how increased A-to-I editing alters the amount and function of proteins for mitochondria, ER-Golgi trafficking and axon/synapse maintenance.
- Test whether combining ER chaperone inducers, pharmacological chaperones that stabilize the lysosomal enzyme GCase, ER-Golgi SNARE trafficking enhancers and direct GCase activators synergistically restores lysosomal activity and lowers a-synuclein in iPSC neurons and mice.
- Establish the dose and duration of lysosomal activation needed for benefit, and develop blood biomarkers that reflect engagement of the target in brain alongside escalating-dose safety assessment in vivo.
- Examine how the unfolded protein response, the cell's alarm for misfolded proteins, relates to GCase solubility and lysosomal delivery, and test whether triggering it restores lysosomal function and reduces a-synuclein in Parkinson's patient neurons.
- Test the hypothesis that reduced glucose flux and reduced N-linked glycosylation of GCase and other lysosomal enzymes contributes to lysosomal depletion in Parkinson's disease.
- Test novel small-molecule activators of the ykt6 trafficking protein and lysosomal biogenesis pathway in patient-derived neurons and in synucleinopathy mouse models.
More about the research
Work here follows the clumping protein a-synuclein through the cell's protein-handling machinery: the endoplasmic reticulum (the folding factory), the transport route from there to the Golgi, and the lysosome (the cell's recycling and disposal compartment). A newer line of work asks how protein clumping in the nucleus changes the chemical editing of RNA messages. Across projects the lab uses neurons grown from patient induced pluripotent stem cells (iPSCs, adult cells reprogrammed into stem cells and then into neurons), mouse models, and post-mortem human brain, with the aim of finding steps that drugs could restore.
Why it matters
Dementia with Lewy bodies, Parkinson's disease and Parkinson's disease dementia have no cure. By tracing how protein aggregates disable the cell's disposal and transport systems and distort RNA editing, this work could identify drug targets and test whether combinations of compounds that restore protein folding, trafficking and lysosomal clearance improve pathology and cognition. It may also yield blood biomarkers of target engagement in the brain and insights relevant to other disorders marked by early synapse loss.
Known grants
From NIH and NSF research grants. Labs often have other funding we can't see.
RNA editing dysregulation in the pathogenesis of Dementia and Parkinson’s disease
NIH · Jun 2026 – May 2031
Synergistic Enhancement of ER proteostasis, trafficking, and lysosomes as treatments for Dementia with Lewy bodies and Parkinson’s disease-dementia
NIH · Aug 2024 – Jul 2027
The role of a-synuclein accumulation in lysosomal hydrolase trafficking and function
NIH · Aug 2015 – Apr 2027
Closest labs
Mohammad Shahnawaz
University of Texas Health Science Center at Houston, TX·Neuroscience
Detect and amplify small amounts of alpha-synuclein strains from body fluids and brain tissue of patients with Parkinson's disease, multiple system atrophy and dementia with Lewy bodies, using the seeding-based PMCA (RT-QuIC) assay.
Smriti Sangwan
Northwestern University, IL·Biochemistry·Early-career
Determine how IRE1, an ER stress sensor, physically connects to the protein-making translational machinery, using single-particle cryo-electron microscopy to resolve the 3D structures involved.
Charleen T Chu
University of Pittsburgh, PA·Neuroscience
Test whether loss of PINK1, a mitochondrial enzyme, impairs the transport of mitochondria into dendrites, using molecular genetic manipulations in Pink1-knockout mouse neurons and patient iPSC-derived cortical neurons.
The school
Northwestern University: 71 labs on PI Pages, $1.3B a year on research, 536 research doctorates a year.
Reach out
A start for your email. Fill in the brackets.