ReviewSpreading of α-synuclein in the face of axonal transport deficits in Parkinson's disease: A speculative synthesis
Introduction
Parkinson's disease (PD) is the second most common adult-onset neurodegenerative disease, for which there is still no cure. The disease is characterized primarily by motor disturbances that are due to the loss of dopamine neurons in the substantia nigra, although non-motor symptoms such as depression are experienced by most patients (Fahn, 2003). While a variety of mechanisms are suggested to contribute to the etiopathogenesis of PD, including impaired protein clearance, axonal transport dysfunction, mitochondrial damage, and inflammation, the specific cause of the disease remains unknown.
Almost all PD patients develop intraneuronal protein aggregates. These proteinaceous inclusions, named Lewy bodies (or Lewy neurites) after their discoverer (Lewy, 1912), are composed primarily of misfolded α-synuclein (α-syn) protein (Goedert et al., 2013, Spillantini et al., 1997). In addition, mutations (A30P, E46K, A53T) or multiplications in the α-syn gene cause autosomal-dominant PD (Hardy et al., 2006). These findings underscore the importance of α-syn in the pathogenesis of PD.
After thorough investigation of α-syn aggregation in post-mortem brains, Braak and colleagues proposed that Lewy pathology propagates throughout the brain in a stereotypic manner (Braak et al., 2003a). Several lines of evidence now suggest that this propagation occurs via a prion-like mechanism, in which misfolded α-syn is responsible for its own pathologic accumulation (Olanow and Brundin, 2013). In order for α-syn pathology to spread over such long distances, it is thought that α-syn aggregates undergo axonal transport (George et al., 2013, Ubeda-Bañon et al., 2013). At the same time, it is proposed that axonal transport is dysfunctional in PD (De Vos et al., 2008, Millecamps and Julien, 2013). How can transport of α-syn aggregates be occurring in the face of general axonal transport dysfunction? In this review, we address this apparent contradiction, and we speculate about the dynamic contribution of axonal transport to PD pathogenesis. We focus our discussion primarily on PD, as the role of axonal transport in other neurodegenerative diseases such as Alzheimer's disease (AD), amyotrophic lateral sclerosis (ALS), and Huntington's disease (HD) has been reviewed extensively elsewhere (De Vos et al., 2008, Millecamps and Julien, 2013, Morfini et al., 2009, Roy et al., 2005).
Section snippets
Fundamentals of axonal transport
Owing to their extreme polarity and long processes, neurons must transport proteins over very long distances. In fact, human neurons can possess axons in excess of 1 m in length. Axonal transport allows neurons to supply essential components to the distal axon and nerve terminals and recycle proteins back to the cell body. Thus, newly synthesized proteins and synaptic vesicles are transported along axons in the anterograde direction (toward the nerve terminal), while recycling organelles such as
Braak staging of PD pathology
In the early 2000s, Braak and colleagues proposed that α-syn pathology spreads through the nervous system in a characteristic fashion as PD progresses (Braak et al., 2003a). These researchers even suggested that the first α-syn aggregates are formed before the affected person experiences any motor symptoms, and therefore before being diagnosed with PD. Specifically, Braak classified idiopathic PD into stages 1–6 according to the presence of Lewy pathology in the brain. In stages 1 and 2, which
Dysfunctional axonal transport contributes to PD pathogenesis
Strict regulation of axonal transport is important for maintaining neuronal structure and function, and therefore it is not surprising that defects in axonal transport are implicated in the pathogenesis of several neurodegenerative diseases, including AD, ALS, and HD (De Vos et al., 2008, Millecamps and Julien, 2013, Morfini et al., 2009, Roy et al., 2005). In the case of PD, several studies in cultured neurons have demonstrated that the transport of α-syn mutants (A30P and A53T) is
Dynamic involvement of axonal transport in PD: a speculative synthesis
Thus far, we have reviewed literature evidence suggesting that axonal transport is both responsible for the progression of α-syn pathology in PD and commonly dysfunctional in PD. How can axonal transport break down over the course of the disease while at the same time contribute to the transfer of α-syn between interconnected brain regions, for which functional transport is presumably required? Although further study is required to address this contradiction, we offer speculation as to how
Therapeutic implications
The notion that axonal transport is dynamically involved in PD pathogenesis presents several new therapeutic possibilities. For instance an agent that blocks the transport of α-syn aggregates may prevent the spread of PD pathology (George et al., 2013), while a molecule that preserves functional axonal transport might slow disease progression (Brunden et al., 2013, Roy et al., 2005). Davunetide, a small molecule that promotes microtubule assembly, restored axonal transport in neuronal cells
Conclusions and future directions
Despite extensive study of axonal transport in various experimental models of PD, several unanswered questions remain. First, though axonal transport probably plays an important role in PD pathogenesis, it does not help to explain why certain neuronal populations such as dopamine neurons of the substantia nigra are especially vulnerable to degeneration in PD. Given that all neurons perform axonal transport, why might axonal transport be altered in some neuronal populations but not others? To
Acknowledgments
JTL is a postdoctoral fellow supported by the Peter C. and Emajean Cook Foundation. ENH is supported by the Van Andel Institute Graduate School. The authors gratefully acknowledge Van Andel Institute for the financial support for their own research in this area.
References (83)
- et al.
Integrating multiple aspects of mitochondrial dynamics in neurons: age-related differences and dynamic changes in a chronic rotenone model
Neurobiol. Dis.
(2011) - et al.
Protein aggregates in Huntington's disease
Exp. Neurol.
(2012) - et al.
The function of α-synuclein
Neuron
(2013) - et al.
Staging of brain pathology related to sporadic Parkinson's disease
Neurobiol. Aging
(2003) - et al.
Axon degeneration in Parkinson's disease
Exp. Neurol.
(2013) - et al.
Spreading of amyloid-β peptides via neuritic cell-to-cell transfer is dependent on insufficient cellular clearance
Neurobiol. Dis.
(2014) - et al.
The rescue of microtubule-dependent traffic recovers mitochondrial function in Parkinson's disease
Biochim. Biophys. Acta
(2014) - et al.
Progressive hyperphosphorylation of neurofilament heavy subunits with aging: possible involvement in the mechanism of neurofilament accumulation
Biochem. Biophys. Res. Commun.
(1995) - et al.
Mitochondrial dysfunction and oxidative stress in Parkinson's disease and monogenic parkinsonism
Neurobiol. Dis.
(2013) - et al.
Transfer of host-derived α-synuclein to grafted dopaminergic neurons in rat
Neurobiol. Dis.
(2011)
Alphaherpesvirus infection disrupts mitochondrial transport in neurons
Cell Host Microbe
Pathogenesis of synaptic degeneration in Alzheimer's disease and Lewy body disease
Biochem. Pharmacol.
α-Synuclein oligomers impair neuronal microtubule-kinesin interplay
J. Biol. Chem.
Mutant huntingtin, abnormal mitochondrial dynamics, defective axonal transport of mitochondria, and selective synaptic degeneration in Huntington's disease
Biochim. Biophys. Acta
Slow axonal transport: fast motors in the slow lane
Curr. Opin. Cell Biol.
Effects of ALS-related SOD1 mutants on dynein- and KIF5-mediated retrograde and anterograde axonal transport
Biochim. Biophys. Acta
Alterations in neurofilament protein immunoreactivity in human hippocampal neurons related to normal aging and Alzheimer's disease
Neuroscience
Exogenous α-synuclein fibrils induce Lewy body pathology leading to synaptic dysfunction and neuron death
Neuron
Dynamic transport and localization of α-synuclein in primary hippocampal neurons
Mol. Neurodegener.
The early events of Alzheimer's disease pathology: from mitochondrial dysfunction to BDNF axonal transport deficits
Neurobiol. Aging
α-Synuclein cell-to-cell transfer and seeding in grafted dopaminergic neurons in vivo
PLoS One
Idiopathic Parkinson's disease: possible routes by which vulnerable neuronal types may be subject to neuroinvasion by an unknown pathogen
J. Neural Transm.
Slow axonal transport: stop and go traffic in the axon
Nat. Rev. Mol. Cell Biol.
Axonal transport of membranous and nonmembranous cargoes: a unified perspective
J. Cell Biol.
Microtubule-stabilizing agents as potential therapeutics for neurodegenerative disease
Bioorg. Med. Chem
A critical evaluation of the Braak staging scheme for Parkinson's disease
Ann. Neurol.
Microtubule alterations occur early in experimental parkinsonism and the microtubule stabilizer epothilone D is neuroprotective
Sci. Rep.
Alterations in axonal transport motor proteins in sporadic and experimental Parkinson's disease
Brain
Dynamic changes in presynaptic and axonal transport proteins combined with striatal neuroinflammation precede dopaminergic neuronal loss in a rat model of AAV α-synucleinopathy
J. Neurosci.
Heat-shock protein 70 modulates toxic extracellular α-synuclein oligomers and rescues trans-synaptic toxicity
FASEB J.
Tumor necrosis factor induces hyperphosphorylation of kinesin light chain and inhibits kinesin-mediated transport of mitochondria
J. Cell Biol.
Familial amyotrophic lateral sclerosis-linked SOD1 mutants perturb fast axonal transport to reduce axonal mitochondria content
Hum. Mol. Genet.
Role of axonal transport in neurodegenerative diseases
Annu. Rev. Neurosci.
Inclusion formation and neuronal cell death through neuron-to-neuron transmission of α-synuclein
Proc. Natl. Acad. Sci. U. S. A.
α-Synuclein imaging: a critical need for Parkinson's disease research
J. Park. Dis.
Description of Parkinson's disease as a clinical syndrome
Ann. N. Y. Acad. Sci.
Neuron-to-neuron transmission of α-synuclein fibrils through axonal transport
Ann. Neurol.
Prion-like mechanisms in neurodegenerative diseases
Nat. Rev. Neurosci.
α-Synuclein: the long distance runner
Brain Pathol.
100 years of Lewy pathology
Nat. Rev. Neurol.
α-Synuclein propagates from mouse brain to grafted dopaminergic neurons and seeds aggregation in cultured human cells
J. Clin. Invest.
Cited by (53)
Can the lack of fibrillar form of alpha-synuclein in Lewy bodies be explained by its catalytic activity?
2022, Mathematical BiosciencesPurine molecules in Parkinson's disease: Analytical techniques and clinical implications
2020, Neurochemistry InternationalCitation Excerpt :Parkinson's Disease (PD) is the second most-prevalent neurodegenerative disorder in patients over 65 years of age (Poewe et al., 2017). The progression of PD is characterized by loss of neurons in the substantia nigra, development of intracellular inclusions of alpha-synuclein, and deficiency in dopamine signaling (Lamberts et al., 2015). PD is clinically diagnosed by the observation of bradykinesia and loss of motor function, but by this point, the disease is in its advanced stages.
Natural alkaloid harmine promotes degradation of alpha-synuclein via PKA-mediated ubiquitin-proteasome system activation
2019, PhytomedicineCitation Excerpt :<alpha>-syn is the major component of Lewy bodies and mutations in the gene encoding <alpha>-syn have been linked to familiar dominant form of PD, <alpha>-syn thus has been regarded to play a central role in the development of PD (Cheng et al., 2011). The role of <alpha>-syn in the etiology and pathogenesis of PD has been extensively studied: <alpha>-syn accumulation may lead to oxidative stress (Esteves et al., 2009), disruption of axonal transport (Lamberts et al., 2015), protein sequestration, mitochondrial dysfunction (Bose and Beal, 2016), synaptic dysfunction (Volpicelli-Daley et al., 2011), and inhibition of the ubiquitin proteasome system (Tanaka et al., 2001b). It is therefore a reasonable strategy to promote clearance of <alpha>-syn for treating PD.
Progress of immunotherapy of anti-α-synuclein in Parkinson's disease
2019, Biomedicine and PharmacotherapyCitation Excerpt :The characteristics of oligomerization and fiber propagation play important roles in PD progression [81,83]. It has been suggested that Lewy pathology originates in the enteric nervous system and spreads to the brain, which would entail an active retrograde transport of α-syn through the vagal nerve [84]. Indeed, human PD brain lysate enriched with different forms of α-syn as well as synthetic α-syn monomers and fibrils injected into the rat intestinal wall resulted in the transport of the exogenous α-syn to the dorsal motor nucleus of the vagus in the brainstem via the vagal nerve [85].
Aging and Parkinson's Disease: Inflammaging, neuroinflammation and biological remodeling as key factors in pathogenesis
2018, Free Radical Biology and Medicine