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.
Join the Team
The Henderson Lab is seeking highly motivated individuals to join our energetic and fast-paced lab as research technicians and postdoctoral fellows. For postdocs, a Ph.D. with molecular and cellular biology or neuroscience experience is required to apply. Additional experience in sterile cell culture, microscopy, neuropathology and/or biochemistry is preferred (but not necessary).
Postdoctoral fellow candidates should reach out to Dr. Henderson. Interested candidates for research technician positions should apply through the VAI Careers Center. Graduate students interested in joining the lab are encouraged to apply to Van Andel Institute Graduate School.
Van Andel Institute, Yale University and University of Pennsylvania scientists awarded grant from Aligning Science Across Parkinson’s
‘Roadmaps’ of the brain reveal regions vulnerable to Alzheimer’s disease
Meet the scientist behind the science: Dr. Michael Henderson
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.
- 171 studies published from Nov. 1, 2020 to Oct. 1, 2021
- 68 studies in high-impact journals from Nov. 1, 2020-Oct. 1, 2021
- 41 clinical trials launched
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
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.
Authors marked with an asterisk contributed equally.
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 factor. Sci 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 neurons. J 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 pathology. Neuron 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 disease. Acta 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 analysis. Nat Neuro 22:1248–1257.
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-synucleinopathies. Neurosci 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 animals. Acta Neuropathol Commun 7:28.
Henderson MX, Peng C, Trojanowski, JQ, Lee VMY. 2018. LRRK2 activity does not dramatically alter α-synuclein pathology in primary neurons. Acta 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 synucleinopathies. J 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 palmitoylation. Acta 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 regulation. Neuron 74:136–150.
Reviewed in: Sheng J, Wu L. 2012. Cysteine string protein α: A new role in vesicle recycling. Neuron 74:6–8.
Assistant Research Technician
Libby Breton, M.S.
Graduate Student Intern
Ashley Douglass, B.S.
Senior Administrative Assistant II
Van Andel Institute Graduate School Student
Van Andel Institute Graduate School Student
Thesis: Identifying structural determinants of tau pathology seeding
Noah Lubben, B.S.
Assistant Research Technician
Lindsay Meyerdirk, M.S.
Alice Prigent, Ph.D.
Alex Soto-Avellaneda, Ph.D.
William Vander Pols
Naman Vatsa, Ph.D.