Studies of patients afflicted by neurodegenerative diseases suggest that misfolded proteins spread through the brain along anatomically connected networks, prompting progressive decline. Recently, mouse models have recapitulated the cell-to-cell transmission of pathogenic proteins and neuron death observed in patients. However, the factors regulating the spread of pathogenic proteins remain a matter of debate due to an incomplete understanding of how vulnerability functions in the context of spread. Here we use quantitative pathology mapping in the mouse brain, combined with network modeling to understand the spatiotemporal pattern of spread. Patterns of α-synuclein pathology are well described by a network model that is based on two factors: anatomical connectivity and endogenous α-synuclein expression. The map and model allow the assessment of selective vulnerability to α-synuclein pathology development and neuron death. Finally, we use quantitative pathology to understand how the G2019S LRRK2 genetic risk factor affects the spread and toxicity of α-synuclein pathology.
Subscribe to Journal
Get full journal access for 1 year
only $4.92 per issue
All prices are NET prices.
VAT will be added later in the checkout.
Tax calculation will be finalised during checkout.
Rent or Buy article
Get time limited or full article access on ReadCube.
All prices are NET prices.
Spillantini, M. G. et al. Filamentous alpha-synuclein inclusions link multiple system atrophy with Parkinson’s disease and dementia with Lewy bodies. Neurosci. Lett. 251, 205–208 (1998).
Spillantini, M. G., Crowther, R. A., Jakes, R., Hasegawa, M. & Goedert, M. alpha-Synuclein in filamentous inclusions of Lewy bodies from Parkinson’s disease and dementia with lewy bodies. Proc. Natl Acad. Sci. USA 95, 6469–6473 (1998).
Baba, M. et al. Aggregation of alpha-synuclein in Lewy bodies of sporadic Parkinson’s disease and dementia with Lewy bodies. Am. J. Pathol. 152, 879–884 (1998).
Rodrigues e Silva, A. M. et al. Who was the man who discovered the “Lewy bodies”? Mov. Disord. 25, 1765–1773 (2010).
Luna, E. & Luk, K. C. Bent out of shape: alpha-synuclein misfolding and the convergence of pathogenic pathways in Parkinson’s disease. FEBS Lett. 589, 3749–3759 (2015).
Surmeier, D. J., Obeso, J. A. & Halliday, G. M. Selective neuronal vulnerability in Parkinson disease. Nat. Rev. Neurosci. 18, 101–113 (2017).
Elstner, M. et al. Neuromelanin, neurotransmitter status and brainstem location determine the differential vulnerability of catecholaminergic neurons to mitochondrial DNA deletions. Mol. Brain 4, 43 (2011).
Luk, K. C. et al. Pathological alpha-synuclein transmission initiates Parkinson-like neurodegeneration in nontransgenic mice. Science 338, 949–953 (2012).
Henderson, M. X. et al. Unbiased proteomics of early Lewy body formation model implicates active microtubule affinity-regulating kinases (MARKs) in synucleinopathies. J. Neurosci. 37, 5870–5884 (2017).
Osterberg, V. R. et al. Progressive aggregation of alpha-synuclein and selective degeneration of lewy inclusion-bearing neurons in a mouse model of parkinsonism. Cell Rep. 10, 1252–1260 (2015).
Rey, N. L. et al. Spread of aggregates after olfactory bulb injection of alpha-synuclein fibrils is associated with early neuronal loss and is reduced long term. Acta Neuropathol. 135, 65–83 (2018).
Tran, H. T. et al. Alpha-synuclein immunotherapy blocks uptake and templated propagation of misfolded alpha-synuclein and neurodegeneration. Cell Rep. 7, 2054–2065 (2014).
Mao, X. et al. Pathological alpha-synuclein transmission initiated by binding lymphocyte-activation gene 3. Science 353, aah3374 (2016).
Li, X. et al. Enhanced striatal dopamine transmission and motor performance with LRRK2 overexpression in mice is eliminated by familial Parkinson’s disease mutation G2019S. J. Neurosci. 30, 1788–1797 (2010).
Henderson, M. X. et al. LRRK2 inhibition does not impart protection from alpha-synuclein pathology and neuron death in non-transgenic mice. Acta Neuropathol. Commun. 7, 28 (2019).
Oh, S. W. et al. A mesoscale connectome of the mouse brain. Nature 508, 207–214 (2014).
Lein, E. S. et al. Genome-wide atlas of gene expression in the adult mouse brain. Nature 445, 168–176 (2007).
Rey, N. L. et al. Widespread transneuronal propagation of alpha-synucleinopathy triggered in olfactory bulb mimics prodromal Parkinson’s disease. J. Exp. Med. 213, 1759–1778 (2016).
Braak, H. et al. Staging of the intracerebral inclusion body pathology associated with idiopathic Parkinson’s disease (preclinical and clinical stages). J. Neurol. 249 (Suppl. 3), III/1–III/5 (2002).
Braak, H. et al. Staging of brain pathology related to sporadic Parkinson’s disease. Neurobiol. Aging 24, 197–211 (2003).
Beach, T. G. et al. Unified staging system for Lewy body disorders: correlation with nigrostriatal degeneration, cognitive impairment and motor dysfunction. Acta Neuropathol. 117, 613–634 (2009).
Healy, D. G. et al. Phenotype, genotype, and worldwide genetic penetrance of LRRK2-associated Parkinson’s disease: a case–control study. Lancet Neurol. 7, 583–590 (2008).
Saunders-Pullman, R. et al. Progression in the LRRK2-asssociated Parkinson disease population. JAMA Neurol. 75, 312–319 (2018).
West, A. B. et al. Parkinson’s disease-associated mutations in leucine-rich repeat kinase 2 augment kinase activity. Proc. Natl Acad. Sci. USA 102, 16842–16847 (2005).
Greggio, E. et al. Kinase activity is required for the toxic effects of mutant LRRK2/dardarin. Neurobiol. Dis. 23, 329–341 (2006).
Sheng, Z. et al. Ser1292 autophosphorylation is an indicator of LRRK2 kinase activity and contributes to the cellular effects of PD mutations. Sci. Transl Med. 4, 164ra161 (2012).
Di Maio, R. et al. LRRK2 activation in idiopathic Parkinson’s disease. Sci. Transl Med. 10, eaar5429 (2018).
Lee, A. J. et al. Penetrance estimate of LRRK2p.G2019S mutation in individuals of non-Ashkenazi Jewish ancestry. Mov. Disord. 32, 1432–1438 (2017).
Volta, M. & Melrose, H. LRRK2 mouse models: dissecting the behavior, striatal neurochemistry and neurophysiology of PD pathogenesis. Biochem. Soc. Trans. 45, 113–122 (2017).
Pandya, S., Mezias, C. & Raj, A. Predictive model of spread of progressive supranuclear palsy using directional network diffusion. Front. Neurol. 8, 692 (2017).
Raj, A., Kuceyeski, A. & Weiner, M. A network diffusion model of disease progression in dementia. Neuron 73, 1204–1215 (2012).
Dagher, A. & Zeighami, Y. Testing the protein propagation hypothesis of Parkinson disease. J. Exp. Neurosci. 12, 1179069518786715 (2018).
Erskine, D. et al. Regional levels of physiological alpha-synuclein are directly associated with Lewy body pathology. Acta Neuropathol. 135, 153–154 (2018).
Tang, E. & Bassett, D. S. Colloquium: control of dynamics in brain networks. Rev. Mod. Phys. 90, 031003 (2018).
Lynn, C. W. & Bassett, D. S. The physics of brain network structure, function and control. Nat. Rev. Phys. 1, 318–332 (2019).
Pang, S. P., Wang, W. X., Hao, F. & Lai, Y. C. Universal framework for edge controllability of complex networks. Sci. Rep. 7, 4224 (2017).
Chen, C. Y. et al. (G2019S) LRRK2 activates MKK4–JNK pathway and causes degeneration of SN dopaminergic neurons in a transgenic mouse model of PD. Cell Death Differ. 19, 1623–1633 (2012).
Ramonet, D. et al. Dopaminergic neuronal loss, reduced neurite complexity and autophagic abnormalities in transgenic mice expressing G2019S mutant LRRK2. PLoS One 6, e18568 (2011).
Xiong, Y. et al. Robust kinase- and age-dependent dopaminergic and norepinephrine neurodegeneration in LRRK2 G2019S transgenic mice. Proc. Natl Acad. Sci. USA 115, 1635–1640 (2018).
Tong, Y. et al. Loss of leucine-rich repeat kinase 2 causes impairment of protein degradation pathways, accumulation of alpha-synuclein, and apoptotic cell death in aged mice. Proc. Natl Acad. Sci. USA 107, 9879–9884 (2010).
Giaime, E. et al. Age-dependent dopaminergic neurodegeneration and impairment of the autophagy–lysosomal pathway in LRRK-deficient mice. Neuron 96, 796–807 e796 (2017).
Volpicelli-Daley, L. A. et al. G2019S-LRRK2 expression augments alpha-synuclein sequestration into inclusions in neurons. J. Neurosci. 36, 7415–7427 (2016).
Bieri, G. et al. LRRK2 modifies α-syn pathology and spread in mouse models and human neurons. Acta Neuropathol. 137, 961–980 (2019).
Novello, S. et al. G2019S LRRK2 mutation facilitates alpha-synuclein neuropathology in aged mice. Neurobiol. Dis. 120, 21–33 (2018).
Benson, D. L., Matikainen-Ankney, B. A., Hussein, A. & Huntley, G. W. Functional and behavioral consequences of Parkinson’s disease-associated LRRK2-G2019S mutation. Biochem. Soc. Trans. 46, 1697–1705 (2018).
Volpicelli-Daley, L. A., Luk, K. C. & Lee, V. M. Addition of exogenous alpha-synuclein preformed fibrils to primary neuronal cultures to seed recruitment of endogenous alpha-synuclein to Lewy body and Lewy neurite-like aggregates. Nat. Protoc. 9, 2135–2146 (2014).
Luk, K. C. et al. Exogenous alpha-synuclein fibrils seed the formation of Lewy body-like intracellular inclusions in cultured cells. Proc. Natl Acad. Sci. USA 106, 20051–20056 (2009).
Volpicelli-Daley, L. A. et al. Exogenous alpha-synuclein fibrils induce Lewy body pathology leading to synaptic dysfunction and neuron death. Neuron 72, 57–71 (2011).
Duda, J. E., Giasson, B. I., Mabon, M. E., Lee, V. M. & Trojanowski, J. Q. Novel antibodies to synuclein show abundant striatal pathology in Lewy body diseases. Ann. Neurol. 52, 205–210 (2002).
Chan, W. H. R., Wildemeersch, M. & Quek, T. Q. S. Characterization and control of diffusion processes in multi-agent networks. Preprint at arXiv https://arxiv.org/abs/1508.06738 (2015).
R Core Team. R: A Language and Environment for Statistical Computing (R Foundation for Statistical Computing, 2017).
Wood, S. N. Generalized Additive Models: An Introduction With R. Vol. 66 (CRC, 2006).
Wood, S. N. Stable and efficient mMultiple smoothing parameter estimation for generalized additive models. J. Am. Stat. Assoc. 99, 673–686 (2004).
Wood, S. N. Fast stable restricted maximum likelihood and marginal likelihood estimation of semiparametric generalized linear models. J. R. Stat. Soc. Ser. B Stat. Methodol. 73, 3–36 (2011).
The authors thank members of the laboratory for their feedback in developing this manuscript. This study was supported by the Michael J. Fox Foundation (9530.01 to M.X.H and V.M.Y.L.) and the following NIH grants: T32-AG000255 (to M.X.H. and V.M.Y.L.), P30-AG010124 (to J.Q.T.) and P50-NS053488 (to V.M.Y.L.). D.S.B. also acknowledges support from the John D. and Catherine T. MacArthur Foundation, the ISI Foundation, the Alfred P. Sloan Foundation, the Paul G. Allen Foundation, the National Institute of Neurological Disorders and Stroke (R01 NS099348), and the National Science Foundation (BCS-1441502, BCS-1430087, NSF PHY-1554488 and BCS-1631550).
The authors declare no competing interests.
Peer review information: Nature Neuroscience thanks Ellen Kuhl, Tiago Outeiro, and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.
Publisher’s note: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
About this article
Cite this article
Henderson, M.X., Cornblath, E.J., Darwich, A. et al. Spread of α-synuclein pathology through the brain connectome is modulated by selective vulnerability and predicted by network analysis. Nat Neurosci 22, 1248–1257 (2019). https://doi.org/10.1038/s41593-019-0457-5
Structural network topology and microstructural alterations of the anterior insula associate with cognitive and affective impairment in Parkinson’s disease
Scientific Reports (2021)
Communications Biology (2021)
Exosome Release Is Modulated by the Mitochondrial-Lysosomal Crosstalk in Parkinson’s Disease Stress Conditions
Molecular Neurobiology (2021)
LRRK2 Ablation Attenuates Αlpha-Synuclein–Induced Neuroinflammation Without Affecting Neurodegeneration or Neuropathology In Vivo
Multiple system atrophy-associated oligodendroglial protein p25α stimulates formation of novel α-synuclein strain with enhanced neurodegenerative potential
Acta Neuropathologica (2021)