Spreading of α-synuclein in the face of axonal transport deficits in Parkinson's disease: A speculative synthesis

doi:10.1016/j.nbd.2014.07.002

Neurobiology of Disease

Volume 77, May 2015, Pages 276-283

https://doi.org/10.1016/j.nbd.2014.07.002 Get rights and content

Abstract

Parkinson's disease (PD) is mainly attributed to degeneration of dopamine neurons in the substantia nigra, but its etiopathogenesis also includes impaired protein clearance and axonal transport dysfunction, among others. The spread of α-synuclein (α-syn) aggregates from one neuron to another, in a prion-like manner, is hypothesized to contribute to PD progression. Axonal transport is likely to play a crucial role in this movement of α-syn aggregates between brain regions. At the same time, deficits in axonal transport are suggested to contribute to neuronal failure in PD. In this review, we discuss the apparent contradiction that axonal transport might be essential for disease progression, while dysfunction of axonal transport could simultaneously be a cornerstone of PD pathogenesis. We speculate around models that reconcile how axonal transport can play such a paradoxical role.

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.

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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.
Parkinson's disease (PD) is a neurodegenerative disorder that primarily affects patients over the age of 65. PD is characterized by loss of neurons in the substantia nigra and dopamine deficiency in the striatum. Once PD is clinically diagnosed by the observation of motor dysfunction, the disease is already in its advance stages. Consequently, there is a major push to identify clinical biomarkers that are useful for the earlier detection of PD. Using untargeted metabolomics, several research groups have identified purine molecules, and specifically urate, as important biomarkers related to PD. This review will summarize recent findings in the field of purine metabolomics and biomarker identification for PD, including in the areas of PD pathophysiology, diagnosis, prognosis and treatment. In addition, this article will summarize and examine the primary research techniques that are employed to quantify purine molecules in both experimental systems and human subjects.
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ReviewSpreading of α-synuclein in the face of axonal transport deficits in Parkinson's disease: A speculative synthesis

Abstract

Introduction

Section snippets

Fundamentals of axonal transport

Braak staging of PD pathology

Dysfunctional axonal transport contributes to PD pathogenesis

Dynamic involvement of axonal transport in PD: a speculative synthesis

Therapeutic implications

Conclusions and future directions

Acknowledgments

Neurobiol. Dis.

Exp. Neurol.

Neuron

Neurobiol. Aging

Exp. Neurol.

Neurobiol. Dis.

Biochim. Biophys. Acta

Biochem. Biophys. Res. Commun.

Neurobiol. Dis.

Neurobiol. Dis.

Cell Host Microbe

Biochem. Pharmacol.

J. Biol. Chem.

Biochim. Biophys. Acta

Curr. Opin. Cell Biol.

Biochim. Biophys. Acta

Neuroscience

Neuron

Mol. Neurodegener.

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.

Review
Spreading of α-synuclein in the face of axonal transport deficits in Parkinson's disease: A speculative synthesis