About

Kelvin C Luk, PhD MTR, is an Associate Professor of Pathology and Laboratory Medicine at the University of Pennsylvania's Perelman School of Medicine. His research aims to improve understanding of synucleinopathies, a group of neurodegenerative disorders including Parkinson’s disease (PD), Lewy body dementia, and multiple system atrophy (MSA). His work focuses on three major themes: the role of protein misfolding in PD and related disorders, the development of novel therapeutics to inhibit the accumulation and transmission of abnormal alpha-synuclein species, and the biology of selective vulnerability in affected cell populations. Dr. Luk's research has demonstrated that aggregated forms of alpha-synuclein are transmissible entities that propagate throughout the brain, akin to prion diseases, which represents a significant shift in understanding PD etiology and progression. His team develops biophysical, cell-based, and animal models to identify factors regulating alpha-synuclein expression, misfolding, transmission routes, and toxicity. Additionally, he collaborates with UPenn’s Center for Neurodegenerative Disease Research Drug Discovery group to develop small molecules and biologicals targeting alpha-synuclein pathology. His research also explores why specific cell populations are vulnerable in synucleinopathies, revealing that connectivity and transcription profiles influence their susceptibility. Dr. Luk holds a BSc in Microbiology and Immunology and a PhD in Pathology from McGill University, as well as a Master’s in Translational Research from the University of Pennsylvania.

Research topics

• Biology
• Chemistry
• Cell biology
• Molecular biology
• Biophysics
• Genetics
• Biochemistry
• Pathology
• Neuroscience
• Medicine

Selected publications

• Additional file 1 of Clinically advanced NLRP3 inhibitor modulates microglial transcriptome and alleviates α-synuclein-induced progression of parkinsonism

  Figshare · 2026-01-31

  articleOpen access

  Supplementary Material 1: Fig S1 to S3.

  PublisherDOI

• Complement Dysregulation During the Early Phases of Synucleinopathy

  bioRxiv (Cold Spring Harbor Laboratory) · 2026-04-30

  articleOpen access

  Abstract Parkinson’s disease (PD) is characterized by progressive degeneration of nigrostriatal dopamine neurons and synucleinopathy, which is the accumulation of aggregated α-synuclein (α-syn). Increasing evidence implicates α-syn-associated neuroinflammation as a contributor to PD pathogenesis; however, immune mechanisms linking synucleinopathy to neurodegeneration remain incompletely defined. Activation of the complement cascade occurs in PD and other neurodegenerative disorders, but most studies report complement activation after overt neurodegeneration, making it difficult to conclude if complement is directly activated by pathological α-syn or secondarily following neurodegeneration. We used the rat α-syn preformed fibril (PFF) mode, in vitro complement assays and human postmortem PD tissue to test whether pathological α-syn directly activates complement prior to overt neurodegeneration. The α-syn PFF model exhibits a protracted pathological time course and distinct temporal separation between peak α-syn aggregation and nigrostriatal degeneration; thus we quantified complement expression, activation, and regulation during the aggregation phase. Synucleinopathy induced complement activation prior to nigrostriatal degeneration, including upregulation of components of both the classical ( C1qa, C1r, C4b ) and alternative ( Cfd, Cfb ) pathways, the anaphylatoxin ( C3aR, C5aR ) and phagocytic ( CR3 ) complement receptors, and activation of complement C3. During early synucleinopathy, microglia upregulated C3 which significantly correlated with synucleinopathy burden across several brain regions, including the substantia nigra pars compacta (SNc) and cortex. Concurrently, complement regulatory proteins, including CD55, CD59, neuronal pentraxin-1 (Nptx1), and the neuronal pentraxin receptor were downregulated in the synucleinopathy-affected SNc. Importantly, increased levels of C1q and iC3b along with downregulation of CD55 and NPTX1 were also observed in human postmortem PD SNc, supporting the translational relevance of our findings. Mechanistically, we demonstrate that aggregated, but not monomeric, α-syn directly binds C1q and activates the complement cascade in a C1q-dpendent manner. These data provide the first in vivo evidence that synucleinopathy triggers complement activation and dysregulation prior to neurodegeneration.

  PublisherOA PDFDOI

• Additional file 1 of Clinically advanced NLRP3 inhibitor modulates microglial transcriptome and alleviates α-synuclein-induced progression of parkinsonism

  Figshare · 2026-01-31

  article

  Supplementary Material 1: Fig S1 to S3.

  DOI

• Clinically advanced NLRP3 inhibitor modulates microglial transcriptome and alleviates α-synuclein-induced progression of parkinsonism

  Figshare · 2026-01-31

  otherOpen access

  Abstract Background Parkinson’s disease (PD), the second most common neurodegenerative disorder after Alzheimer’s disease, and the rare disorder multiple system atrophy (MSA), are both characterized by intracellular accumulation of α-synuclein fibrils and early, sustained microglial reactivity in parallel to the neurodegeneration. Activation of the NLRP3 inflammasome in disease-associated reactive microglia is increasingly recognized as a key pathogenic driver and a promising therapeutic target in synucleinopathies. Dapansutrile (OLT1177®) is a selective, orally bioavailable NLRP3 inhibitor with a favorable safety profile in clinical trials for non-neurological indications. Here, we evaluated the therapeutic potential of dapansutrile in preclinical models of PD and MSA and explored the predictive and translational value of its effects. Methods Two established mouse models of synucleinopathy with nigral neurodegeneration were employed: the α-synuclein preformed fibril (PFF) propagation model and the transgenic PLP-α-syn model expressing human wild-type α-synuclein in oligodendrocytes. Pharmacokinetic analyses assessed plasma and brain exposure after oral administration. The efficacy of six-month dapansutrile treatment was examined in both preventive (post-PFF injection) and therapeutic (PLP-α-syn mice) paradigms, using behavioral, histopathological, and molecular readouts. Transcriptomic profiling of striatal and midbrain microglia identified differentially expressed genes (DEGs) associated with treatment and compared them with post-mortem transcriptomic signatures of disease-associated microglia in PD patients. Plasma IL-18 and neurofilament light chain (NfL) levels were evaluated as translational biomarkers. Results Chronic oral dapansutrile treatment at clinically relevant doses improved motor performance, reduced α-synuclein inclusions, attenuated gliosis, and mitigated nigral neurodegeneration in both models. Microglial transcriptomic analyses revealed that dapansutrile reversed key transcriptional signatures characteristic of PD-associated reactive microglia. Moreover, plasma IL-18 and NfL levels correlated with neuropathological and functional outcomes, supporting their potential as biomarkers of target engagement and treatment efficacy. Conclusions These data identify chronic NLRP3 activation as a shared and targetable mechanism in PD and MSA and highlight dapansutrile as a CNS-penetrant, clinically advanced candidate for disease modification in α-synucleinopathies. The observed transcriptomic reprogramming of microglia and the parallel changes in blood biomarkers provide a strong translational bridge to clinical development.

  PublisherDOI

• Intestinal macrophages modulate synucleinopathy along the gut–brain axis

  Nature · 2026-01-28 · 6 citations

  articleOpen access
  PublisherOA PDFDOI

• Testing an inverse link between limbic alpha-synucleinopathy and myelin markers in mice and humans

  npj Parkinson s Disease · 2026-02-17

  articleOpen access

  In Lewy body disease, alpha-synucleinopathic inclusions tend to develop in brain regions that extend long, thin, and unmyelinated projection fibers, but it is not known if this selective vulnerability is caused by poor myelination status. Our objective was to investigate this link in the limbic forebrain. First, we observed that levels of insoluble, hyperphosphorylated alpha-synuclein correlated inversely with the myelin marker proteolipid protein (20 kDa isoform) in the amygdala of men (but not women) with Lewy body disease. Second, select oligodendrocytic markers were mildly suppressed in the amygdala of men with Lewy body disease. Third, preformed fibrils (PFFs) of alpha-synuclein tended to induce greater pathology in gray matter, even when infused into murine brain regions penetrated by myelinated fiber bundles. Given these correlative patterns, we tested the hypothesis that myelin disruption with pharmacologic or genetic tools will exacerbate the development of limbic alpha-synucleinopathy in mice of both sexes, using a full-factorial experimental design. In nontransgenic mice with retrobulbar infusions of PFFs, dietary exposure to the established myelin disruptor cuprizone modestly increased the fraction of Triton-insoluble alpha-synuclein that was hyperphosphorylated at serine 129 (pSer129). Contrary to our hypothesis, however, cuprizone did not induce systematic, robust worsening of most pSer129+ object attributes, behavior deficits, cellular toxicity measures (NeuN+/Hoechst+ object attributes), or pan-alpha-synuclein insolubility. Similarly, PFF-induced effects on the insolubility and hyperphosphorylation of alpha-synuclein, behavior measures, and pSer129+, NeuN+, and Hoechst+ object attributes were not markedly amplified in mice heterozygous for the shiverer mutation in myelin basic protein (Mbp+/shi), compared to wild-type littermates. Although alpha-synucleinopathy is negatively associated with select myelin markers in mice and men, the causal nature of this link thus remains to be verified, and its potential implications are discussed here.

  PublisherOA PDFDOI

• Clinically advanced NLRP3 inhibitor modulates microglial transcriptome and alleviates α-synuclein-induced progression of parkinsonism

  Figshare · 2026-01-31

  otherOpen access

  Abstract Background Parkinson’s disease (PD), the second most common neurodegenerative disorder after Alzheimer’s disease, and the rare disorder multiple system atrophy (MSA), are both characterized by intracellular accumulation of α-synuclein fibrils and early, sustained microglial reactivity in parallel to the neurodegeneration. Activation of the NLRP3 inflammasome in disease-associated reactive microglia is increasingly recognized as a key pathogenic driver and a promising therapeutic target in synucleinopathies. Dapansutrile (OLT1177®) is a selective, orally bioavailable NLRP3 inhibitor with a favorable safety profile in clinical trials for non-neurological indications. Here, we evaluated the therapeutic potential of dapansutrile in preclinical models of PD and MSA and explored the predictive and translational value of its effects. Methods Two established mouse models of synucleinopathy with nigral neurodegeneration were employed: the α-synuclein preformed fibril (PFF) propagation model and the transgenic PLP-α-syn model expressing human wild-type α-synuclein in oligodendrocytes. Pharmacokinetic analyses assessed plasma and brain exposure after oral administration. The efficacy of six-month dapansutrile treatment was examined in both preventive (post-PFF injection) and therapeutic (PLP-α-syn mice) paradigms, using behavioral, histopathological, and molecular readouts. Transcriptomic profiling of striatal and midbrain microglia identified differentially expressed genes (DEGs) associated with treatment and compared them with post-mortem transcriptomic signatures of disease-associated microglia in PD patients. Plasma IL-18 and neurofilament light chain (NfL) levels were evaluated as translational biomarkers. Results Chronic oral dapansutrile treatment at clinically relevant doses improved motor performance, reduced α-synuclein inclusions, attenuated gliosis, and mitigated nigral neurodegeneration in both models. Microglial transcriptomic analyses revealed that dapansutrile reversed key transcriptional signatures characteristic of PD-associated reactive microglia. Moreover, plasma IL-18 and NfL levels correlated with neuropathological and functional outcomes, supporting their potential as biomarkers of target engagement and treatment efficacy. Conclusions These data identify chronic NLRP3 activation as a shared and targetable mechanism in PD and MSA and highlight dapansutrile as a CNS-penetrant, clinically advanced candidate for disease modification in α-synucleinopathies. The observed transcriptomic reprogramming of microglia and the parallel changes in blood biomarkers provide a strong translational bridge to clinical development.

  PublisherDOI

• Clinically advanced NLRP3 inhibitor modulates microglial transcriptome and alleviates α-synuclein-induced progression of parkinsonism

  Journal of Neuroinflammation · 2026-01-31 · 1 citations

  articleOpen access

  Parkinson’s disease (PD), the second most common neurodegenerative disorder after Alzheimer’s disease, and the rare disorder multiple system atrophy (MSA), are both characterized by intracellular accumulation of α-synuclein fibrils and early, sustained microglial reactivity in parallel to the neurodegeneration. Activation of the NLRP3 inflammasome in disease-associated reactive microglia is increasingly recognized as a key pathogenic driver and a promising therapeutic target in synucleinopathies. Dapansutrile (OLT1177®) is a selective, orally bioavailable NLRP3 inhibitor with a favorable safety profile in clinical trials for non-neurological indications. Here, we evaluated the therapeutic potential of dapansutrile in preclinical models of PD and MSA and explored the predictive and translational value of its effects. Two established mouse models of synucleinopathy with nigral neurodegeneration were employed: the α-synuclein preformed fibril (PFF) propagation model and the transgenic PLP-α-syn model expressing human wild-type α-synuclein in oligodendrocytes. Pharmacokinetic analyses assessed plasma and brain exposure after oral administration. The efficacy of six-month dapansutrile treatment was examined in both preventive (post-PFF injection) and therapeutic (PLP-α-syn mice) paradigms, using behavioral, histopathological, and molecular readouts. Transcriptomic profiling of striatal and midbrain microglia identified differentially expressed genes (DEGs) associated with treatment and compared them with post-mortem transcriptomic signatures of disease-associated microglia in PD patients. Plasma IL-18 and neurofilament light chain (NfL) levels were evaluated as translational biomarkers. Chronic oral dapansutrile treatment at clinically relevant doses improved motor performance, reduced α-synuclein inclusions, attenuated gliosis, and mitigated nigral neurodegeneration in both models. Microglial transcriptomic analyses revealed that dapansutrile reversed key transcriptional signatures characteristic of PD-associated reactive microglia. Moreover, plasma IL-18 and NfL levels correlated with neuropathological and functional outcomes, supporting their potential as biomarkers of target engagement and treatment efficacy. These data identify chronic NLRP3 activation as a shared and targetable mechanism in PD and MSA and highlight dapansutrile as a CNS-penetrant, clinically advanced candidate for disease modification in α-synucleinopathies. The observed transcriptomic reprogramming of microglia and the parallel changes in blood biomarkers provide a strong translational bridge to clinical development.

  PublisherDOI

• Cell vulnerability within the sublaterodorsal tegmental nucleus underlies REM sleep behaviour disorder in prodromal α-synucleinopathy

  bioRxiv (Cold Spring Harbor Laboratory) · 2026-05-01

  articleOpen accessSenior author

  REM sleep behaviour disorder (RBD) is a prodromal manifestation of α-synucleinopathies such as Parkinson's disease. Evidence suggests that degeneration of REM sleep regulating neurons in the sublaterodorsal tegmental nucleus (SLD) could give rise to RBD, yet the specific cellular populations involved and their contribution to synucleinopathy progression remain unclear. Here, we investigated the role of defined SLD cell types in RBD pathogenesis. Using viral vector and fibril-based models of α-synucleinopathy, we show that α-synuclein pathology in SLD neurons triggers RBD in mice. Notably, glutamatergic SLD neurons are selectively vulnerable to synucleinopathy and the loss of these cells correlates with RBD severity. Propagation of synucleinopathy from the SLD to midbrain and forebrain structures leads to the emergence of neurological deficits associated with Parkinson's disease. These findings establish that SLD neurons are critical substrates for RBD and provide insight into the cellular mechanisms at play in the early stages of synucleinopathies.

  PublisherOA PDFDOI

• IFNγ alters the aberrant phenotype of α-synuclein–treated microglia reducing the detrimental impact of their secretome on dopaminergic neurons

  Neuroscience · 2026-03-28

  articleOpen access

  Microglia play a major role in the pathophysiology of Parkinson's disease, where they regulate both α-synuclein (αSyn) aggregate clearance and inflammatory responses. Interferon gamma (IFNγ) is a strong immunomodulator, but its role in shaping human microglial phenotypes during αSyn exposure remains incompletely understood. Further, whether the secreted factors from microglia after exposure to αSyn pre-formed fibrils (PFFs) and IFNγ can affect morphology and functionality of dopaminergic neurons has not been studied. We used human stem cell-derived microglia to investigate how αSyn PFFs and IFNγ stimulation influence microglial metabolism, lipid composition, and phenotypic state. IFNγ induced broad metabolic and lipidomic remodeling, affecting glycolytic, tryptophan, and phospholipid pathways. Pre-exposure to IFNγ promoted a resolving-like phenotype upon αSyn PFFs challenge, characterized by increased transglutaminase 2 (TGM2) expression and elevated TGFβ1 secretion. Conditioned media (CM) from exposed microglia were applied to human iPSC-derived dopaminergic neurons, and neuronal morphology, protein expression, mitochondrial function, and electrophysiological activity were evaluated. CM from αSyn PFFs-exposed microglia reduced neuronal branching and neurite length. Furthermore, CM from stimulated microglia decreased TUJ1 and TH expression, altered mitochondrial regulators (cytochrome C, MnSOD, iNOS), and disrupted neuronal activity as measured by changes in c-FOS expression and multielectrode array recordings. IFNγ profoundly modulates human microglial states, enhancing resolving-like features and simultaneously driving secretome-mediated neuronal effects. These findings highlight microglial activation state as a critical determinant of neuronal vulnerability in αSyn-associated pathology. Importantly, IFNγ-induced microglial activation can, at least partially, counteract αSyn-driven adverse effects on dopaminergic neurons.

  PublisherDOI

Recent grants

• Propagation of Lewy pathology in Parkinson's and related disorders

  NIH · $4.0M · 2015–2026

Frequent coauthors

• Virginia M.‐Y. Lee

  California University of Pennsylvania

  106 shared

• John Q. Trojanowski

  University of Pennsylvania

  94 shared

• Bin Zhang

  Icahn School of Medicine at Mount Sinai

  42 shared

• Abbas F. Sadikot

  39 shared

• Caryl E. Sortwell

  Michigan State University

  33 shared

• Norihito Uemura

  University of Pennsylvania

  30 shared

• Vladimir V. Rymar

  26 shared

• Nicholas P. Marotta

  University of Pennsylvania

  24 shared

Education

• MTR

  University of Pennsylvania

  2013

• PhD

  McGill University

  2004