Henderson Laboratory

Protein Pathologies and Genetic Risk in Neurodegeneration

Parkinson’s disease (PD) and dementia with Lewy bodies (DLB) are progressive neurodegenerative diseases affecting movement and cognitive function in patients. These two diseases share a common pathology — aggregates bearing misfolded forms of the normally synaptic protein α-synuclein. While these diseases begin gradually, they progress relentlessly, and this progression of symptoms is associated with the accumulation of misfolded α-synuclein in more and more regions of the brain and the misfolding of additional proteins, including tau.

PD and DLB bear an additional commonality — the lack of disease-modifying treatments. Substantial evidence suggests that either disrupting the formation of protein pathologies or the transmission of pathology through the brain will result in stabilization, and perhaps improvement, of symptoms. Susceptibility to these diseases depends on several factors, including genetic background. Mutations in proteins like leucine-rich repeat kinase 2 (LRRK2) and glucocerebrosidase can predispose individuals to developing PD or DLB and targeting these proteins may provide therapeutic benefit for patients as well.

The Henderson Laboratory takes a two-pronged approach to addressing neurodegenerative disease. One approach is to understand what goes wrong in neurons and the brain to lead to neurodegeneration by probing disrupted cellular pathways, mapping how pathology spreads through the brain and investigating the impact of genetic risk factors on disease progression. The second approach is to use what we learn about these diseases to develop and evaluate potential therapeutic treatments. The laboratory utilizes primary neuron cultures to investigate cellular pathways disrupted in disease and screen therapeutic molecules. We also use animal models of disease to understand how pathological proteins spread through the brain and to evaluate the likely efficacy of top therapeutic candidates. It is the mission of the Henderson Laboratory to use rigorous scientific methods to understand neurodegenerative diseases and to leverage that knowledge to develop and evaluate treatments for these devastating diseases.

Recent Tweets

Our Impact

We’re raising thousands to save millions.

We’re turning hope into action for the millions of people around the world affected by diseases like cancer and Parkinson’s. Find out how you can help us make a difference.

  • 120 peer-reviewed papers published in 2023
  • 62 peer-reviewed papers published in high-impact journals in 2023
  • 55 clinical trials launched to date

Michael Henderson, Ph.D.

Assistant Professor, Department of Neurodegenerative Science

Areas of Expertise

Parkinson’s disease (PD), neurodegenerative disease models, pathological protein cell-to-cell transmission, LRRK2, GBA1, α-synuclein, tau

Biography

Michael Henderson is a neuroscientist whose focus is on the impact of protein pathologies and genetic risk factors on the development and progression of neurodegenerative diseases. He earned his B.Sc. in biological science from Florida State, followed by his Ph.D. in neuroscience from Yale University. He conducted his doctoral research in the lab of Dr. Sreeganga Chandra, and moved to the University of Pennsylvania for his postdoctoral fellowship in the Center for Neurodegenerative Disease Research with Drs. Virginia Lee and John Trojanowski. In 2020, Dr. Henderson joined Van Andel Institute’s Center for Neurodegenerative Science as an assistant professor.

Dr. Henderson has made several seminal contributions to neurodegenerative disease research, including the identification of palmitoyl-protein thioesterase 1 as a protein aggregate in adult-onset neuronal ceroid lipofuscinosis, the demonstration that α-synuclein pathology spreads through anatomical connectivity in the brain, and the demonstration that glucocerebrosidase acts as a modulator of α-synuclein pathogenesis.

He has received several awards and honors, including the Graduate Research Fellowship from the National Science Foundation and the Ruth L. Kirschstein National Research Service Award for predoctoral research.

Selected Publications

Authors marked with an asterisk contributed equally.

Goralski TM, Meyerdirk L, Breton L, Brasseur L, Kurgat K, DeWeerd D, Turner L, Becker K, Adams M, Newhouse DJ, Henderson MX. 2024. Spatial transcriptomics reveals molecular dysfunction associated with cortical Lewy pathology. Nat Commun 15:2642.

Leyns CG, Prigent A, Beezhold B, Yao L, Hatcher NG, Tao P, Kang J, Suh E, Van Deerlin VM, Trojanowski JQ, Lee VMY, Kennedy ME, Fell MJ, Henderson MX. 2023. Glucocerebrosidase activity and lipid levels are related to protein pathologies in Parkinson’s disease. NPJ Parkinson’s Dis 9(1):74.

Peelaerts W, Mercado G, George S, Villumsen M, Kasen A, Aguileta, Linstow C, Sutter AB, Kuhn E, Stetzik L, Sheridan R, Bergkvist L, Meyerdirk L, Lindqvist A, Escobar Galvis ML, Van den Haute C, Hultgren SJ, Baekelandt V, Pospisilik JA, Brudek T, Aznar S, Steiner JA, Henderson MX, Brundin L, Ivanova MI, Hannan TJ, Brundin P. 2023. Urinary tract infections trigger synucleinopathy via the innate immune response. Acta Neuropathol 6.

Chen L, Nagaraja C, Daniels S, Fisk ZA, Dvorak R, Meyerdirk L, Steiner JA, Escobar Galvis ML, Henderson MX, Rousseaux MWC, Brundin P, Chu HY. 2022. Synaptic location is a determinant of the detrimental effects of α-synuclein pathology to glutamatergic transmission in the basolateral amygdala. eLife 11:e78055.

Henderson MX, Henrich MT, Geibl FF, Oertel WH, Brundin P, Surmeier DJ. 2022. The roles of connectivity and neuronal phenotype in determining the pattern of α-synuclein pathology in Parkinson’s disease. Neurobiol Dis 168:105687.

Stetzik L, Mercado G, Smith L, George S, Quansah E, Luda K, Schulz E, Meyerdirk L, Lindquist A, Bergsma A, Jones RG, Brundin L, Henderson MX, Pospisilik JA, Brundin P. 2022. A novel automated morphological analysis of IBA1+ microglia using a deep learning assisted model. Front Cell Neurosci 16:944875.

Chen L, Nagaraja C, Daniels S, Fisk ZA, Dvorak R, Meyerdirk L, Steiner JA, Escobar Galvis ML, Henderson MX, Rousseaux MWC, Brundin P, Chu HY. 2022. Synaptic location is a determinant of the detrimental effects of α-synuclein pathology to glutamatergic transmission in the basolateral amygdala. eLife11:e78055.

Cornblath EJ, Li HL, Changolkar L, Zhang B, Brown HJ, Gathagan RJ, Olufemi MF, Trojanowski JQ, Bassett DS, Lee VYM, Henderson MX. 2021. Computational modeling of tau pathology spread reveals patterns of regional vulnerability and the impact of a genetic risk factorSci Adv 7(24):eabg6677.

Henderson MX, Changolkar L, Trojanowski JQ, Lee VMY. In press. LRRK2 kinase activity does not alter cell-autonomous tau pathology development in primary neuronsJ Parkinson’s Dis.

Henderson MX, Sedor S, McGeary I, Cornblath EJ, Peng C, Riddle DM, Li HL, Zhang B, Brown H, Olufemi MF, Bassett DS, Trojanowski JQ, Lee VMY. 2020. Glucocerebrosidase activity modulates neuronal vulnerability to α-synuclein pathologyNeuron 105:1–15.

Henderson MX, Covell DJ, Chung CHY, Pitkin RM, Sandler RM, Decker SC, Riddle DM, Zhang B, Gathagan RJ, James MJ, Trojanowski JQ, Brunden K, Lee VMY, Luk K. 2020. Characterization of novel conformation-selective α-synuclein antibodies as potential immunotherapeutic agents for Parkinson’s disease. Neurobiol Dis 136:104712.

Henderson MX, Sengupta M, Trojanowski JQ, Lee VMY. 2019. Alzheimer’s disease tau is a prominent pathology in LRRK2 Parkinson’s diseaseActa Neuropathol Commun 7(1):183.

Henderson MX, Cornblath EJ, Darwich A, Zhang B, Brown H, Gathagan H, Sandler R, Bassett DS, Trojanowski JQ, Lee VMY. 2019. Spread of α-synuclein pathology through the brain connectome is modulated by selective vulnerability and predicted by network analysisNat Neuro 22:1248–1257.
Reviewed in:
Kuhl, E. 2019. 
Connectomics of neurodegeneration. Nat Neuro 22:1200–1202.
Lempriere S. 2019. Connectivity and vulnerability determine α-synuclein spread. Nat Rev Neurol.  

Henderson MX, Trojanowski JQ, Lee VMY. 2019. α-Synuclein pathology in Parkinson’s disease and related α-synucleinopathiesNeurosci Lett 709:134316.

Henderson MX, Sengupta M, McGeary I, Zhang B, Olufemi MF, Brown H, Trojanowski, JQ, Lee VMY. 2019. LRRK2 inhibition does not impart protection from α-synuclein pathology and neuron death in non-transgenic animalsActa Neuropathol Commun 7:28.

Henderson MX, Peng C, Trojanowski, JQ, Lee VMY. 2018. LRRK2 activity does not dramatically alter α-synuclein pathology in primary neuronsActa Neuropathol Commun 6:45.

Henderson MX, Chung CH-Y, Riddle DM, Zhang B, Gathagan RJ, Seeholzer SH, Trojanowski, JQ, Lee VMY. 2017. Unbiased proteomics of early Lewy body formation model implicates active microtubule affinity-regulating kinases (MARKs) in synucleinopathiesJ Neurosci 37(24):5870–5884.

Henderson MX*, Wirak GS*, Zhang YQ, Dai F, Ginsberg SD, Dolzhanskaya N, Staropoli JF, Nijssen PC, Lam TT, Roth AF, Davis NG, Dawson G, Velinov M, Chandra SS. 2016. Neuronal ceroid lipofuscinosis with DNAJC5/CSPα mutation has PPT1 pathology and exhibit aberrant protein palmitoylationActa Neuropathol 131(4):621–637.

Zhang Y*, Henderson MX*, Colangelo CM, Ginsberg S, Bruce C, Wu T, Chandra SC. 2012. Identification of CSPα clients reveals a role in dynamin 1 regulationNeuron 74:136–150.
Reviewed in: Sheng J, Wu L. 2012. Cysteine string protein α: A new role in vesicle recycling. Neuron 74:6–8.

Laura Brasseur

Assistant Research Technician, Department of Neurodegenerative Science

Libby Breton, M.S.

Research Technician, Department of Neurodegenerative Science

Ashley Douglass, B.S.

Senior Administrative Assistant II

Thomas Goralski, M.S.

Ph.D. Candidate, VAI Graduate School

Thesis project title to be determined

Alysa Kasen

Ph.D. Candidate, VAI Graduate School

Thesis: Identifying structural determinants of tau pathology seeding

Kevin Kurgat

Assistant Research Technician, Department of Neurodegenerative Science

Lindsay Meyerdirk, M.S.

Lab Manager, Department of Neurodegenerative Science

Alice Prigent, Ph.D.

Postdoctoral Fellow, Henderson Laboratory

Alex Soto-Avellaneda, Ph.D.

Postdoctoral Fellow, Henderson Laboratory

Naman Vatsa, Ph.D.

Postdoctoral Fellow, Henderson Laboratory

Parkinson's disease

Lab Alumni

Brenna Beezhold

Intern

Natalie Currie

Intern

Daniella DeWeerd

Bioinformatics Analyst

Noah Lubben, B.S.

Assistant Research Technician

Devin McGee

Research Technician

Claire Noe

Intern

Lillian Sauline

Intern

Noah Schautz

Intern

Feehaan Sultan

Intern

Will Vander Pols

Intern